2,180 results on '"Leukemia, Myeloid metabolism"'
Search Results
2. Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway.
- Author
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Jiang YX, Zhao YN, Yu XL, and Yin LM
- Subjects
- Animals, Humans, Cell Line, Tumor, Mice, Extracellular Signal-Regulated MAP Kinases metabolism, Cell Survival drug effects, Leukemia, Myeloid pathology, Leukemia, Myeloid drug therapy, Leukemia, Myeloid metabolism, MAP Kinase Signaling System drug effects, Ginsenosides pharmacology, Glycogen Synthase Kinase 3 beta metabolism, Cell Differentiation drug effects, Signal Transduction drug effects
- Abstract
Objective: To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation., Methods: AML cells were treated with GRd (25, 50, 100 and 200 µg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), GSK3β and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg·d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg·d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining., Results: The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (p<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (p<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01)., Conclusion: GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
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3. The transcriptome of acute dehydration in myeloid leukemic cells.
- Author
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Mark Welch DB, Gould TJ, Olins AL, and Olins DE
- Subjects
- Humans, Dehydration genetics, HL-60 Cells, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Osmotic Pressure physiology, Sucrose metabolism, Transcriptome
- Abstract
Human myeloid leukemia cells (HL-60/S4) exposed to hyperosmotic stress with sucrose undergo dehydration and cell shrinkage. Interphase chromatin and mitotic chromosomes congeal, exhibiting altered phase separation (demixing) of chromatin proteins. To investigate changes in the transcriptome, we exposed HL-60/S4 cells to hyperosmotic sucrose stress (~600 milliOsmolar) for 30 and 60 minutes. We employed RNA-Seq of polyA mRNA to identify genes with increased or decreased transcript levels relative to untreated control cells (i.e., differential gene expression). These genes were examined for over-representation of Gene Ontology (GO) terms. In stressed cells, multiple GO terms associated with transcription, translation, mitochondrial function and proteosome activity, as well as "replication-dependent histones", were over-represented among genes with increased transcript levels; whereas, genes with decreased transcript levels were over-represented with transcription repressors. The transcriptome profiles of hyperosmotically-stressed cells suggest acquisition of cellular rebuilding, a futile homeostatic response, as these cells are ultimately doomed to a dehydrated death.
- Published
- 2024
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4. miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 S expression.
- Author
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Sessa R, Trombetti S, Bianco AL, Amendola G, Catapano R, Cesaro E, Petruzziello F, D'Armiento M, Maruotti GM, Menna G, Izzo P, and Grosso M
- Subjects
- Humans, Down Syndrome genetics, Down Syndrome complications, Down Syndrome pathology, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Leukemoid Reaction complications, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1
S ). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1S , we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1S . These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1S levels.- Published
- 2024
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5. Capsazepine activates amiloride-insensitive ENaC-like channels in human leukemia cells.
- Author
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Lysikova DV, Vasileva VY, Chubinskiy-Nadezhdin VI, Morachevskaya EA, and Sudarikova AV
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- Humans, Epithelial Sodium Channels genetics, Epithelial Sodium Channels metabolism, Sodium metabolism, Oocytes metabolism, Amiloride pharmacology, Amiloride metabolism, Leukemia, Myeloid metabolism
- Abstract
Sodium influx carried out by ion channels is one of the main regulators of water-salt and volume balance in cells of blood origin. Previously, we described amiloride-insensitive ENaC-like channels in human myeloid leukemia K562 cells; the intracellular regulatory mechanisms of the channels are associated with actin cytoskeleton dynamics. Recently, an extracellular mechanism of ENaC-like channels activation in K562 cells by the action of serine protease trypsin has been revealed. The other extracellular pathways that modulate ENaC (epithelial Na
+ channel) activity and sodium permeability in transformed blood cells are not yet fully investigated. Here, we study the action of capsazepine (CPZ), as δ-ENaC activator, on single channel activity in K562 cells in whole-cell patch clamp experiments. Addition of CPZ (2 μM) to the extracellular solution caused an activation of sodium channels with typical features; unitary conductance was 15.1 ± 0.8 pS. Amiloride derivative benzamil (50 μM) did not inhibit their activity. Unitary currents and conductance of CPZ-activated channels were higher in Na+ -containing extracellular solution than in Li+ , that is one of the main fingerprints of δ-ENaC. The results of RT-PCR analysis and immunofluorescence staining also confirmed the expression of δ-hENaC (as well as α-, β-, γ-ENaC) at the mRNA and protein level. These findings allow us to speculate that CPZ activates amiloride-insensitive ENaC-like channels that contain δ-ENaC in К562 cells. Our data reveal a novel extracellular mechanism for ENaC-like activation in human leukemia cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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6. Expansions of tumor-reactive Vdelta1 gamma-delta T cells in newly diagnosed patients with chronic myeloid leukemia.
- Author
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Knight A, Piskacek M, Jurajda M, Prochazkova J, Racil Z, Zackova D, and Mayer J
- Subjects
- Humans, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Receptors, Antigen, T-Cell, gamma-delta metabolism, T-Lymphocyte Subsets, Cell Line, Leukemia, Myeloid metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
- Abstract
Recent studies have underscored the importance of gamma-delta (γδ) T cells in mediating potent MHC-unrestricted cytotoxicity in numerous malignancies. Here, we analyzed Vδ1 and Vδ2 γδ T cell subsets in newly diagnosed chronic myeloid leukemia (CML) patients (n = 40) who had initiated tyrosine kinase inhibitor (TKI) therapy including imatinib (n = 22), nilotinib (n = 14) and dasatinib (n = 4). Patient peripheral blood samples were analyzed at diagnosis and monitored prospectively at 3, 6, 12 and 18 months post-TKI. γδ T cells isolated from healthy donors and CML patients were used against K562, LAMA-84 and KYO-1 cell lines and against primary CML cells in cytotoxicity assays. We found large expansions of Vδ1 and Vδ2 T cells in patients at diagnosis compared to age-matched healthy donors (n = 40) (p < 0.0001). The γδ T cell reconstitution in patients on imatinib and also on nilotinib showed significant reductions of Vδ1 T cell and Vδ2 T cell absolute counts at 3 months compared to diagnosis. Importantly, Vδ1 and Vδ2 T absolute cell counts remained at normal levels from 3 months throughout the follow-up. Next, we observed susceptibility to specific lysis of primary CML tumor cells by Vδ1 T cells from healthy donors. Furthermore, we determined inherent cytotoxic reactivity by autologous patients' Vδ1 T lymphocytes against primary CML tumor cells. Finally, the TCR clonality profiles showed in CML patients mostly polyclonal repertoires regardless of the TKI. Our results provide further evidence into γδ T cell antileukemia immunity in CML that might be beneficial for long-term disease control and treatment outcome., (© 2022. The Author(s).)
- Published
- 2023
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7. Novel endogenous endoplasmic reticulum transmembrane protein SURF4 suppresses cell death by negatively regulating the STING-STAT6 axis in myeloid leukemia.
- Author
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Kim J, Lee H, Hong CM, Nam JH, Yeo HJ, Cho WH, Kim HS, Hong C, Kim YH, and Lee D
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- Humans, Endoplasmic Reticulum metabolism, Cell Death, STAT6 Transcription Factor metabolism, Membrane Proteins metabolism, Leukemia, Myeloid metabolism
- Published
- 2023
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8. Naturally Occurring Bicoumarin Compound Daphnoretin Inhibits Growth and Induces Megakaryocytic Differentiation in Human Chronic Myeloid Leukemia Cells.
- Author
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Huang YC, Huang CP, Lin CP, Yang KC, Lei YJ, Wang HP, Kuo YH, and Chen YJ
- Subjects
- Humans, Dimethyl Sulfoxide pharmacology, Cell Differentiation, Antiviral Agents pharmacology, Leukemia, Myeloid metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Daphnoretin extracted from the stem and roots of Wikstroemia indica (L.) C.A. Mey has been shown to possess antiviral and antitumor activities. Herein, we hypothesized that daphnoretin might induce megakaryocytic differentiation, thereby inhibiting the proliferation of cells and serving as a differentiation therapy agent for chronic myeloid leukemia (CML). Daphnoretin-treated K562 and HEL cells were examined for growth inhibition, cell morphology, and megakaryocyte-specific markers. Potential mechanisms of megakaryocytic differentiation of daphnoretin-treated K562 cells were evaluated. The results showed that daphnoretin inhibited the growth of K562 and HEL cells in a dose- and time-dependent manner. Flow cytometry analyses revealed that daphnoretin treatment slightly increased the proportion of sub-G1 and polyploid cells compared to that of dimethyl sulfoxide (DMSO)-treated control cells. Morphological examination showed that daphnoretin-treated K562 and HEL cells exhibited enlarged contours and multinucleation as megakaryocytic characteristics compared to DMSO-treated control cells. Daphnoretin treatment also dramatically enhanced the expression of megakaryocytic markers CD61 and CD41. Under optimal megakaryocytic differentiation conditions, daphnoretin increased the phosphorylation of STAT3 but not STAT5. In summary, daphnoretin inhibited cell growth and induced megakaryocytic differentiation in K562 and HEL cells. The efficacy of daphnoretin in vivo and in patients with CML may need further investigations for validation.
- Published
- 2022
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9. Precision medicine in myeloid malignancies.
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Westermann J and Bullinger L
- Subjects
- Humans, Precision Medicine, Tretinoin therapeutic use, Tumor Microenvironment genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid metabolism, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute genetics
- Abstract
Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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10. SIRT2 regulates proliferation and chemotherapy response of MLL-ENL-driven acute myeloid leukemia.
- Author
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Hao C, Shao X, Song J, Peng M, Lao Y, Mack R, Zhang L, Wei W, Liu N, Wang T, Wu Y, Feng L, Yin L, Wang S, Sun X, Chen S, Zhang J, and Li B
- Subjects
- Acute Disease, Amino Acid Sequence, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinogenesis genetics, Carcinogenesis metabolism, Carcinogenesis pathology, Cytarabine administration & dosage, Doxorubicin administration & dosage, Gene Expression Regulation, Leukemic drug effects, Kaplan-Meier Estimate, Leukemia, Myeloid drug therapy, Leukemia, Myeloid metabolism, Mice, Inbred C57BL, Mice, Knockout, Myeloid-Lymphoid Leukemia Protein metabolism, Oncogene Proteins, Fusion metabolism, Sequence Homology, Amino Acid, Sirtuin 2 metabolism, Tumor Cells, Cultured, Mice, Cell Proliferation genetics, Gene Expression Regulation, Leukemic genetics, Leukemia, Myeloid genetics, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics, Sirtuin 2 genetics
- Abstract
Both MLL-AF9 and MLL-ENL leukemia fusion proteins drive oncogenic transformation of hematopoietic cells through their N-terminal DNA/histone binding mixed-lineage leukemia 1 domain and C-terminal fragment of AF9 or ENL containing an unstructured linker region and the ANC1 homology domain, which recruits transcription factors. Despite of their structural similarity, acute myeloid leukemia (AML) patients bearing MLL-ENL show more adverse outcomes compared to those with MLL-AF9. We recapitulated the clinical patterns of these two MLL-fusions driven AMLs using murine models and found that MLL-ENL AML cells showed slower cell cycle progression and more resistance to standard chemotherapy than MLL-AF9 cells. These phenotypes were primarily controlled by the linker regions of ENL and a highly conserved lysine residue K469 within. Substitution of K469 with an acetylated mimic glutamine abolished the ability of MLL-ENL to suppress proliferation and promote chemo-resistance. We showed that deacetylase Sirt2 might act as an upstream regulator of MLL-ENL. Deletion of Sirt2 promoted proliferation of AML cells with either MLL fusions. Importantly, loss of Sirt2 greatly enhanced the sensitivity of the MLL-ENL AML cells to chemo-treatment. Taken together, our study uncovered a unique regulatory role of Sirt2 in leukemogenesis and suggested targeting SIRT2 as a new way to sensitize MLL-ENL AML patience for chemotherapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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11. Azoxystrobin Induces Apoptosis and Cell Cycle Arrest in Human Leukemia Cells Independent of p53 Expression.
- Author
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Takahashi S, Shinomiya T, and Nagahara Y
- Subjects
- HL-60 Cells, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Leukemia, T-Cell metabolism, Leukemia, T-Cell pathology, Signal Transduction, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Proliferation drug effects, Leukemia, Myeloid drug therapy, Leukemia, T-Cell drug therapy, Pyrimidines pharmacology, Strobilurins pharmacology, Tumor Suppressor Protein p53 metabolism
- Abstract
Background/aim: Azoxystrobin (AZOX), a methoxyacrylate derivative, has potent antimicrobial and antitumor activities. Here, we report the anticancer effects of AZOX on the p53-negative human myelogenous leukemia cell line HL-60RG and the p53 positive human T-cell leukemia cell line MOLT-4F., Materials and Methods: Using both leukemia cells, the anticancer effect of AZOX treatment was analyzed throughout the cell cycle., Results: AZOX damaged both cell lines dose-dependently, and the cell damage rates were almost the same in both lines. Cell cycle distribution analysis showed that the treated MOLT-4F cells arrested at the S phase, whereas HL-60RG cells increased during the subG1 phase, suggesting that cell death was occurring. AZOX-induced cell death in HL-60RG was inhibited with the addition of uridine, which is used as a substrate for the salvage pathway of pyrimidine nucleotides., Conclusion: AZOX has p53-independent anticancer effects in leukemia cells, but the mechanisms underlying the damage differ between cell lines., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2022
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12. CD99 in malignant hematopoiesis.
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Ali A, Vaikari VP, and Alachkar H
- Subjects
- 12E7 Antigen analysis, 12E7 Antigen genetics, Animals, Gene Expression Regulation, Leukemic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Leukemia, Myeloid therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, 12E7 Antigen metabolism, Hematopoiesis, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Myeloid metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Published
- 2022
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13. Iron deficiency as promoter of heavy metals-induced acute myeloid leukemia.
- Author
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Cirovic A and Cirovic A
- Subjects
- Acute Disease, Anemia, Iron-Deficiency complications, Anemia, Iron-Deficiency metabolism, Antigens, CD metabolism, Bone Marrow Cells metabolism, Cadmium metabolism, Erythroblasts metabolism, Humans, Lead metabolism, Leukemia, Myeloid etiology, Leukemia, Myeloid metabolism, Metals, Heavy metabolism, Models, Biological, Receptors, Transferrin metabolism, Anemia, Iron-Deficiency blood, Cadmium blood, Cell Transformation, Neoplastic, Lead blood, Leukemia, Myeloid blood, Metals, Heavy blood
- Abstract
Iron deficiency (ID) and iron deficiency anemia (IDA) have many adverse effects on human health. Also, iron deficiency anemia and anemia in general are linked with an increased risk of various cancers, particularly blood cancers. It is known that subjects with IDA as well as smokers have elevated blood levels of toxic divalent cations, particularly cadmium (Cd
2+ ) and lead (Pb2+ ). Cadmium is a proven carcinogen. Most of the circulating cadmium is bound to transferrin and apart from the target organs of cadmium accumulation, kidney and liver, tissues (cells) which highly express transferrin receptor 1 (TfR1) may also accumulate high levels of circulating cadmium. Density of TfR1, glycoprotein that is expressed on cell surface, is not uniform in bone marrow cells. Namely, megakaryocyte/erythrocyte progenitors and pro-erythroblasts express TfR1 incomparably more than other cell lines within the bone marrow and we hypothesize that the mentioned cell lines will uptake most of the circulating cadmium and lead, and will consequently be most suitable for malignant transformation. In this review, we discuss in detail the mechanisms involved in accumulation of cadmium in particular cell lines of the bone marrow and the consequent occurrence of acute myeloid leukemia (AML)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2022
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14. Decreased CD177 pos neutrophils in myeloid neoplasms is associated with NPM1, RUNX1, TET2, and U2AF1 S34F mutations.
- Author
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Alayed K and Meyerson HJ
- Subjects
- Acute Disease, Aged, Female, Flow Cytometry methods, GPI-Linked Proteins metabolism, High-Throughput Nucleotide Sequencing methods, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Leukocyte Count, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Neutrophils pathology, Core Binding Factor Alpha 2 Subunit genetics, DNA-Binding Proteins genetics, Dioxygenases genetics, Isoantigens metabolism, Leukemia, Myeloid genetics, Mutation, Neutrophils metabolism, Nucleophosmin genetics, Receptors, Cell Surface metabolism, Splicing Factor U2AF genetics
- Abstract
A decreased percentage of CD177
pos neutrophils is frequently present in MDS and AML and is a useful flow cytometry (FCM) marker for the identification of MDS. The underlying mechanism leading to the low percentage of CD177pos neutrophils in MDS has not been explained. The aim of this study was to identify whether specific somatic mutations in myeloid neoplasms are associated with the low percentage of CD177pos neutrophils. 507 myeloid neoplasms with one or more pathogenic molecular abnormality identified by NGS and in which CD177 expression was assessed were evaluated. Correlation with CD177 expression was determined for 39 variables (including genes mutated, diagnostic groups and gender) using a 40 % cutoff level for low CD177 expression. In multivariate analysis mutations involving NPM1 (OD 0.26), RUNX1 (OD 0.39), TET2 (OD 0.58), and U2AF1 S34F (OD 0.25) were associated with low percentage of CD177pos neutrophils when all cases were evaluated. JAK2 (OD 2.5) alteration was associated with increased percentage of CD177pos neutrophils. Differences were noted between diagnostic subgroups with no single mutation associated with decreased CD177pos neutrophils in MDS and CCUS. The findings demonstrate an association between the percentage of CD177pos neutrophils and somatically acquired mutations involving several genes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2022
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15. Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.
- Author
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Pemovska T, Bigenzahn JW, Srndic I, Lercher A, Bergthaler A, César-Razquin A, Kartnig F, Kornauth C, Valent P, Staber PB, and Superti-Furga G
- Subjects
- Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Survival drug effects, Cluster Analysis, Fatty Acids biosynthesis, Genotype, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Monocarboxylic Acid Transporters genetics, Phenotype, Phosphatidylinositol 3-Kinase metabolism, Phosphoinositide-3 Kinase Inhibitors metabolism, Phosphoinositide-3 Kinase Inhibitors pharmacology, Pyrimidinones metabolism, Pyrimidinones pharmacology, Pyrrolidines metabolism, Pyrrolidines pharmacology, Signal Transduction, Small Molecule Libraries classification, Symporters genetics, Systems Analysis, Thiophenes metabolism, Thiophenes pharmacology, Triazoles metabolism, Triazoles pharmacology, Tumor Cells, Cultured, Leukemia, Myeloid metabolism, Small Molecule Libraries metabolism, Small Molecule Libraries pharmacology
- Abstract
Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds. We, next, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Analysis of the drug response profiles reveals that 77 drugs affect cell viability, with the top effective compounds targeting nucleic acid synthesis, oxidative stress, and the PI3K/mTOR pathway. Clustering of individual drug response profiles stratifies the cell lines into five functional groups, which link to specific molecular and metabolic features. Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large., (© 2021. The Author(s).)
- Published
- 2021
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16. Clinical and biological aspects of myeloid leukemia in Down syndrome.
- Author
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Boucher AC, Caldwell KJ, Crispino JD, and Flerlage JE
- Subjects
- Humans, Leukemia, Myeloid etiology, Leukemia, Myeloid metabolism, Down Syndrome complications, GATA1 Transcription Factor genetics, Leukemia, Myeloid pathology, Mutation
- Abstract
Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal myelopoiesis (TAM), which is self-limited expansion of fetal liver-derived megakaryocyte progenitors. An array of international studies has led to consensus in treating ML-DS with reduced-intensity chemotherapy, leading to excellent outcomes. In addition, studies performed in the past 20 years have revealed many of the genetic and epigenetic features of the tumors, including GATA1 mutations that are arguably associated with all cases of both TAM and ML-DS. Despite these advances in understanding the clinical and biological aspects of ML-DS, little is known about the mechanisms of relapse. Upon relapse, patients face a poor outcome, and there is no consensus on treatment. Future studies need to be focused on this challenging aspect of leukemia in children with DS., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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17. The Fusion of CLEC12A and MIR223HG Arises from a trans -Splicing Event in Normal and Transformed Human Cells.
- Author
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Dhungel BP, Monteuuis G, Giardina C, Tabar MS, Feng Y, Metierre C, Ho S, Nagarajah R, Fontaine ARM, Shah JS, Gokal D, Bailey CG, Schmitz U, and Rasko JEJ
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Differentiation genetics, Cell Line, Cytarabine pharmacology, Humans, Lectins, C-Type metabolism, Leukemia, Myeloid metabolism, MicroRNAs metabolism, Mutant Chimeric Proteins metabolism, Receptors, Mitogen metabolism, Transcriptional Activation, Gene Fusion, Lectins, C-Type genetics, Leukemia, Myeloid genetics, MicroRNAs genetics, Mutant Chimeric Proteins genetics, Receptors, Mitogen genetics, Trans-Splicing
- Abstract
Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A-MIR223HG , a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA-223 host gene ( MIR223HG ), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A-MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A-MIR223HG expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that CLEC12A-MIR223HG is a product of trans -splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A-MIR223HG expression. CLEC12A-MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein-protein interactions. Taken together, our observations support a possible involvement of CLEC12A-MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs.
- Published
- 2021
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18. A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia.
- Author
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Zeng Y, Zhang X, Lin D, Feng X, Liu Y, Fang Z, Zhang W, Chen Y, Zhao M, Wu J, and Jiang L
- Subjects
- Animals, Antibiotics, Antineoplastic therapeutic use, Cell Line, Tumor, Doxorubicin therapeutic use, Drug Delivery Systems, Drug Resistance, Neoplasm, Humans, Leukemia, Myeloid metabolism, Zebrafish, Antibiotics, Antineoplastic administration & dosage, Delayed-Action Preparations chemistry, Dextrans chemistry, Doxorubicin administration & dosage, Leukemia, Myeloid drug therapy, Lysosomes metabolism
- Abstract
The hypoxic microenvironment is presumed to be a sanctuary for myeloid leukemia cells that causes relapse following chemotherapy, but the underlying mechanism remains elusive. Using a zebrafish xenograft model, we observed that the hypoxic hematopoietic tissue preserved most of the chemoresistant leukemic cells following the doxorubicin (Dox) treatment. And hypoxia upregulated TFEB, a master regulator of lysosomal biogenesis, and increased lysosomes in leukemic cells. Specimens from relapsed myeloid leukemia patients also harbored excessive lysosomes, which trapped Dox and prevented drug nuclear influx leading to leukemia chemoresistance. Pharmaceutical inhibition of lysosomes enhanced Dox-induced cytotoxicity against leukemic cells under hypoxia circumstance. To overcome lysosome associated chemoresistance, we developed a pH-sensitive dextran-doxorubicin nanomedicine (Dex-Dox) that efficiently released Dox from lysosomes and increased drug nuclear influx. More importantly, Dex-Dox treatment significantly improved the chemotherapy outcome in the zebrafish xenografts transplanted with cultured leukemic cells or relapsed patient specimens. Overall, we developed a novel lysosome targeting nanomedicine that is promising to overcome the myeloid leukemia chemoresistance., (© 2021. The Author(s).)
- Published
- 2021
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19. Mechanical stiffness softening and cell adhesion are coordinately regulated by ERM dephosphorylation in KG-1 cells.
- Author
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Kihara T, Matsumoto T, Nakahashi Y, and Tachibana K
- Subjects
- Actins metabolism, Amides pharmacology, Cell Adhesion genetics, Cell Line, Tumor, Cytochalasin D pharmacology, Elasticity drug effects, Fibronectins metabolism, Humans, Leukemia, Myeloid metabolism, Microvilli drug effects, Microvilli metabolism, Phorbol Esters pharmacology, Phosphorylation drug effects, Pyridines pharmacology, Staurosporine pharmacology, Cell Adhesion drug effects, Cell Adhesion physiology, Cytoskeletal Proteins metabolism, Elasticity physiology, Leukemia, Myeloid pathology, Leukocytes metabolism, Leukocytes physiology, Membrane Proteins metabolism, Microfilament Proteins metabolism
- Abstract
Mechanical stiffness is closely related to cell adhesion and rounding in some cells. In leukocytes, dephosphorylation of ezrin/radixin/moesin (ERM) proteins is linked to cell adhesion events. To elucidate the relationship between surface stiffness, cell adhesion, and ERM dephosphorylation in leukocytes, we examined the relationship in the myelogenous leukemia line, KG-1, by treatment with modulation drugs. KG-1 cells have ring-shaped cortical actin with microvilli as the only F-actin cytoskeleton, and the actin structure constructs the mechanical stiffness of the cells. Phorbol 12-myristate 13-acetate and staurosporine, which induced cell adhesion to fibronectin surface and ERM dephosphorylation, caused a decrease in surface stiffness in KG-1 cells. Calyculin A, which inhibited ERM dephosphorylation and had no effect on cell adhesion, did not affect surface stiffness. To clarify whether decreasing cell surface stiffness and inducing cell adhesion are equivalent, we examined KG-1 cell adhesion by treatment with actin-attenuated cell softening reagents. Cytochalasin D clearly diminished cell adhesion, and high concentrations of Y27632 slightly induced cell adhesion. Only Y27632 slightly decreased ERM phosphorylation in KG-1 cells. Thus, decreasing cell surface stiffness and inducing cell adhesion are not equivalent, but these phenomena are coordinately regulated by ERM dephosphorylation in KG-1 cells., (© 2021. Japan Human Cell Society.)
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- 2021
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20. Human mesenchymal stem cells derived exosomes inhibit the growth of acute myeloid leukemia cells via regulating miR-23b-5p/TRIM14 pathway.
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Cheng H, Ding J, Tang G, Huang A, Gao L, Yang J, and Chen L
- Subjects
- 3' Untranslated Regions genetics, Acute Disease, Adult, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation genetics, Cells, Cultured, Exosomes metabolism, Female, HL-60 Cells, Humans, Intracellular Signaling Peptides and Proteins metabolism, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Male, MicroRNAs genetics, Middle Aged, RNA Interference, Signal Transduction genetics, THP-1 Cells, Tripartite Motif Proteins metabolism, Young Adult, Exosomes genetics, Gene Expression Regulation, Leukemic, Intracellular Signaling Peptides and Proteins genetics, Leukemia, Myeloid genetics, Mesenchymal Stem Cells metabolism, Tripartite Motif Proteins genetics
- Abstract
Background: Acute myeloid leukemia (AML) is a malignancy commonly seen in adults. Previous studies indicated that TRIM14 played a tumorigenic role in various types of cancer and miR-23b-5p was down-regulated in human mesenchymal stem cell-derived exosomes (HMSC-exos) of AML patients. However, their roles in AML remains unclear. Our study aims to investigate the role of TRIM14 and miR-23b-5p in the pathogenesis of AML., Materials and Methods: The blood specimen was collected from de novo AML patients and healthy donators. Exosomes were extracted from the culture medium of human mesenchymal stem cells under ultracentrifugation. Then exosomes were co-cultured with AML cells to determine the effect of their contents. The cell proliferation was detected by cell counting kit-8 assay, whereas the cell apoptosis was detected by flow cytometry. The expression of miR-23b-5p and TRIM14 was silenced or overexpressed to explore their biological functions in AML. Luciferase reporter assay was conducted to validate the interaction between miR-23b-5p and TRIM14. Gene expression was determined by quantitative real-time PCR and immunoblots., Results: TRIM14 was significantly increased in AML patients and cell lines. The inhibition of TRIM14 significantly reduced the proliferation and induced the apoptosis of AML cells via activating PI3K/AKT pathway, whereas its overexpression exhibited reversed effects. HMSC-exos could suppress the proliferation of AML cells through the delivery of miR-23b-5p. Moreover, miR-23b-5p inhibited the transcription of TRIM14 by binding on its 3'UTR region. Overexpression of TRIM14 exhibited reversed effect against the function of miR-23b-5p mimic., Conclusion: TRIM14 could promote the proliferation of AML cells via activating PI3K/AKT pathway, which was reversed by HMSC-exos through delivering miR-23b-5p. These findings indicated that miR-23b-5p and TRIM14 could be applied as potential targets for the treatment of AML., (© 2021. The Author(s).)
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- 2021
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21. Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia.
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Lipreri da Silva JC, Coelho-Silva JL, Lima K, Vicari HP, Lazarini M, Costa-Lotufo LV, Traina F, and Machado-Neto JA
- Subjects
- Acute Disease, Adamantane analogs & derivatives, Adamantane pharmacology, Adult, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Cytoskeletal Proteins antagonists & inhibitors, Cytoskeletal Proteins metabolism, Disease-Free Survival, Female, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid diagnosis, Leukemia, Myeloid metabolism, Male, Phenols pharmacology, Prognosis, Quinolines pharmacology, Quinolones pharmacology, THP-1 Cells, U937 Cells, Biomarkers, Tumor genetics, Cytoskeletal Proteins genetics, Cytoskeleton metabolism, Gene Expression Regulation, Leukemic, Genes, Regulator genetics, Leukemia, Myeloid genetics
- Abstract
Purpose: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML., Methods: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays., Results: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells., Conclusions: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs., (© 2021. Springer Nature Switzerland AG.)
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- 2021
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22. RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner.
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Abdallah MG, Niibori-Nambu A, Morii M, Yokomizo T, Yokomizo T, Ideue T, Kubota S, Teoh VSI, Mok MMH, Wang CQ, Omar AA, Tokunaga K, Iwanaga E, Matsuoka M, Asou N, Nakagata N, Araki K, AboElenin M, Madboly SH, Sashida G, and Osato M
- Subjects
- Age Factors, Animals, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Mice, Mice, Knockout, Translocation, Genetic, Core Binding Factor Alpha 2 Subunit physiology, DNA-Binding Proteins genetics, Leukemia, Myeloid pathology, Oncogene Proteins, Fusion, Proto-Oncogene Proteins genetics, RUNX1 Translocation Partner 1 Protein physiology, Transcription Factors genetics
- Published
- 2021
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23. The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops.
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Ottema S, Mulet-Lazaro R, Erpelinck-Verschueren C, van Herk S, Havermans M, Arricibita Varea A, Vermeulen M, Beverloo HB, Gröschel S, Haferlach T, Haferlach C, J Wouters B, Bindels E, Smeenk L, and Delwel R
- Subjects
- Acute Disease, CCCTC-Binding Factor metabolism, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 8 genetics, Gene Expression Regulation, Leukemic, Gene Rearrangement, High-Throughput Nucleotide Sequencing methods, Humans, In Situ Hybridization, Fluorescence methods, K562 Cells, Karyotyping, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Promoter Regions, Genetic genetics, Protein Binding, Translocation, Genetic, CCCTC-Binding Factor genetics, Enhancer Elements, Genetic genetics, Leukemia, Myeloid genetics, MDS1 and EVI1 Complex Locus Protein genetics, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogenes genetics
- Abstract
Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis., (© 2021. The Author(s).)
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- 2021
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24. The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors.
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Khateb A, Deshpande A, Feng Y, Finlay D, Lee JS, Lazar I, Fabre B, Li Y, Fujita Y, Zhang T, Yin J, Pass I, Livneh I, Jeremias I, Burian C, Mason JR, Almog R, Horesh N, Ofran Y, Brown K, Vuori K, Jackson M, Ruppin E, Deshpande AJ, and Ronai ZA
- Subjects
- Acute Disease, Animals, Cell Line, Tumor, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, HEK293 Cells, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid drug therapy, Leukemia, Myeloid metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, U937 Cells, Ubiquitin-Protein Ligases metabolism, Mice, Genetic Predisposition to Disease genetics, Histone Deacetylase Inhibitors pharmacology, Leukemia, Myeloid genetics, Ubiquitin-Protein Ligases genetics, Xenograft Model Antitumor Assays methods
- Abstract
Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9-driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors., (© 2021. The Author(s).)
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- 2021
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25. Cohesin mutations in myeloid malignancies.
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Jann JC and Tothova Z
- Subjects
- Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells pathology, Humans, Cohesins, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism, Hematologic Neoplasms genetics, Hematologic Neoplasms metabolism, Hematologic Neoplasms pathology, Hematologic Neoplasms therapy, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Leukemia, Myeloid therapy, Mutation, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, Myeloproliferative Disorders pathology, Myeloproliferative Disorders therapy, Neoplasm Proteins genetics, Neoplasm Proteins metabolism
- Abstract
Cohesin is a multisubunit protein complex that forms a ring-like structure around DNA. It is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation, and DNA damage repair and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1, and SMC3, as well as its modulators PDS5A/B, WAPL, and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down syndrome-associated acute megakaryoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and de novo and secondary acute myeloid leukemias. The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells, which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Herein, we review the role of the cohesin complex in healthy and malignant hematopoiesis. We discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting., (© 2021 by The American Society of Hematology.)
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- 2021
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26. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways.
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Miyamoto R, Kanai A, Okuda H, Komata Y, Takahashi S, Matsui H, Inaba T, and Yokoyama A
- Subjects
- Animals, Carcinogenesis genetics, Female, Gene Expression Regulation, Leukemic, HEK293 Cells, Homeodomain Proteins genetics, Humans, Leukemia, Myeloid metabolism, Mice, Mice, Inbred C57BL, Myeloid-Lymphoid Leukemia Protein genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, SOXC Transcription Factors genetics, SOXC Transcription Factors metabolism, Cell Transformation, Neoplastic metabolism, Homeodomain Proteins metabolism, Neoplasm Proteins metabolism, Transcription Factors
- Abstract
HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, BCL2 and SOX4 synergistically induced leukemia with MYC . Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias., Competing Interests: RM, AK, HO, YK, ST, HM, TI No competing interests declared, AY received a research grant from Dainippon Sumitomo Pharma Co. Ltd., (© 2021, Miyamoto et al.)
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- 2021
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27. Mapping the cellular origin and early evolution of leukemia in Down syndrome.
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Wagenblast E, Araújo J, Gan OI, Cutting SK, Murison A, Krivdova G, Azkanaz M, McLeod JL, Smith SA, Gratton BA, Marhon SA, Gabra M, Medeiros JJF, Manteghi S, Chen J, Chan-Seng-Yue M, Garcia-Prat L, Salmena L, De Carvalho DD, Abelson S, Abdelhaleem M, Chong K, Roifman M, Shannon P, Wang JCY, Hitzler JK, Chitayat D, Dick JE, and Lechman ER
- Subjects
- Animals, Antigens, CD34 analysis, Cell Cycle Proteins metabolism, Cell Lineage, Cell Proliferation, Cell Transformation, Neoplastic, Chromosomal Proteins, Non-Histone genetics, Chromosomes, Human, Pair 21 genetics, Chromosomes, Human, Pair 21 metabolism, Disease Models, Animal, Disease Progression, Down Syndrome complications, Female, GATA1 Transcription Factor metabolism, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Heterografts, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Liver embryology, Male, Megakaryocytes physiology, Mice, MicroRNAs genetics, MicroRNAs metabolism, Mutation, Preleukemia metabolism, Preleukemia pathology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Mas, Proto-Oncogene Proteins c-kit analysis, Proto-Oncogene Proteins c-kit antagonists & inhibitors, Cohesins, Cell Cycle Proteins genetics, Down Syndrome genetics, GATA1 Transcription Factor genetics, Hematopoietic Stem Cells physiology, Leukemia, Myeloid genetics, Preleukemia genetics
- Abstract
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 ( GATA1 ) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117
+ /KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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28. Omics Technologies to Decipher Regulatory Networks in Granulocytic Cell Differentiation.
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Novikova S, Tikhonova O, Kurbatov L, Farafonova T, Vakhrushev I, Lupatov A, Yarygin K, and Zgoda V
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Gene Expression genetics, Gene Expression Profiling methods, Gene Expression Regulation, Leukemic genetics, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Proteomics methods, Transcription Factors metabolism, Cell Differentiation physiology, Gene Regulatory Networks genetics, Leukemia, Myeloid metabolism
- Abstract
Induced granulocytic differentiation of human leukemic cells under all- trans -retinoid acid (ATRA) treatment underlies differentiation therapy of acute myeloid leukemia. Knowing the regulation of this process it is possible to identify potential targets for antileukemic drugs and develop novel approaches to differentiation therapy. In this study, we have performed transcriptomic and proteomic profiling to reveal up- and down-regulated transcripts and proteins during time-course experiments. Using data on differentially expressed transcripts and proteins we have applied upstream regulator search and obtained transcriptome- and proteome-based regulatory networks of induced granulocytic differentiation that cover both up-regulated (HIC1, NFKBIA, and CASP9) and down-regulated (PARP1, VDR, and RXRA) elements. To verify the designed network we measured HIC1 and PARP1 protein abundance during granulocytic differentiation by selected reaction monitoring (SRM) using stable isotopically labeled peptide standards. We also revealed that transcription factor CEBPB and LYN kinase were involved in differentiation onset, and evaluated their protein levels by SRM technique. Obtained results indicate that the omics data reflect involvement of the DNA repair system and the MAPK kinase cascade as well as show the balance between the processes of the cell survival and apoptosis in a p53-independent manner. The differentially expressed transcripts and proteins, predicted transcriptional factors, and key molecules such as HIC1, CEBPB, LYN, and PARP1 may be considered as potential targets for differentiation therapy of acute myeloid leukemia.
- Published
- 2021
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29. Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.
- Author
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Penter L, Zhang Y, Savell A, Huang T, Cieri N, Thrash EM, Kim-Schulze S, Jhaveri A, Fu J, Ranasinghe S, Li S, Zhang W, Hathaway ES, Nazzaro M, Kim HT, Chen H, Thurin M, Rodig SJ, Severgnini M, Cibulskis C, Gabriel S, Livak KJ, Cutler C, Antin JH, Nikiforow S, Koreth J, Ho VT, Armand P, Ritz J, Streicher H, Neuberg D, Hodi FS, Gnjatic S, Soiffer RJ, Liu XS, Davids MS, Bachireddy P, and Wu CJ
- Subjects
- Allogeneic Cells, Female, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid therapy, Male, CD8-Positive T-Lymphocytes metabolism, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen genetics, CTLA-4 Antigen metabolism, Gene Expression Regulation, Leukemic drug effects, Hematopoietic Stem Cell Transplantation, Ipilimumab administration & dosage, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism
- Abstract
Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.
- Published
- 2021
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30. Targeted Therapeutic Approach Based on Understanding of Aberrant Molecular Pathways Leading to Leukemic Proliferation in Patients with Acute Myeloid Leukemia.
- Author
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Song MK, Park BB, and Uhm JE
- Subjects
- Acute Disease, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism, Sulfonamides therapeutic use, United States, United States Food and Drug Administration, Antineoplastic Agents therapeutic use, Cell Proliferation drug effects, Leukemia, Myeloid drug therapy, Molecular Targeted Therapy methods, Signal Transduction drug effects
- Abstract
Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.
- Published
- 2021
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31. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.
- Author
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Stuani L, Sabatier M, Saland E, Cognet G, Poupin N, Bosc C, Castelli FA, Gales L, Turtoi E, Montersino C, Farge T, Boet E, Broin N, Larrue C, Baran N, Cissé MY, Conti M, Loric S, Kaoma T, Hucteau A, Zavoriti A, Sahal A, Mouchel PL, Gotanègre M, Cassan C, Fernando L, Wang F, Hosseini M, Chu-Van E, Le Cam L, Carroll M, Selak MA, Vey N, Castellano R, Fenaille F, Turtoi A, Cazals G, Bories P, Gibon Y, Nicolay B, Ronseaux S, Marszalek JR, Takahashi K, DiNardo CD, Konopleva M, Pancaldi V, Collette Y, Bellvert F, Jourdan F, Linares LK, Récher C, Portais JC, and Sarry JE
- Subjects
- Acute Disease, Aminopyridines pharmacology, Animals, Cell Line, Tumor, Doxycycline pharmacology, Drug Resistance, Neoplasm drug effects, Enzyme Inhibitors pharmacology, Epigenesis, Genetic drug effects, Glycine analogs & derivatives, Glycine pharmacology, HL-60 Cells, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase metabolism, Isoenzymes antagonists & inhibitors, Isoenzymes genetics, Isoenzymes metabolism, Leukemia, Myeloid drug therapy, Leukemia, Myeloid metabolism, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mitochondria drug effects, Mitochondria metabolism, Oxadiazoles pharmacology, Oxidative Phosphorylation drug effects, Piperidines pharmacology, Pyridines pharmacology, Triazines pharmacology, Xenograft Model Antitumor Assays methods, Mice, Drug Resistance, Neoplasm genetics, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid genetics, Mitochondria genetics, Mutation
- Abstract
Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors., Competing Interests: Disclosures: B. Nicolay reported "other" from Agios Pharmaceuticals outside the submitted work and is an employee and shareholder of Agios Pharmaceuticals. J.R. Marszalek reported a patent to IACS-010759 issued. K. Takahashi reported personal fees from Celgene during the conduct of the study; and personal fees from Symbio Pharmaceuticals, GSK, and Novartis outside the submitted work. C.D. DiNardo reported personal fees from Agios Pharmaceuticals, Celgene, and AbbVie outside the submitted work. M. Konopleva reported "other" from Amgen, Kisoji, and Reata Pharmaceutical; and grants from AbbVie, Genentech, and Stemline Therapeutics, F. Hoffman La-Roche, Forty Seven, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, and Sanofi outside the submitted work. In addition, M. Konopleva had a patent to Novartis pending (62/993,166), a patent to Eli Lilly issued, and a patent to Reata Pharmaceutical issued (7,795,305 B2 CDDO). C. Récher reported grants from Celgene, Amgen, Novartis, Jazz, AbbVie, Astellas, MaatPharma, Agios, Daiichi-Sankyo, and Roche; personal fees from Incyte, Macrogenics, Otsuka, Janssen, Pfizer, and Takeda; and non-financial support from Sanofi and Gilead outside the submitted work. No other disclosures were reported., (© 2021 Stuani et al.)
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- 2021
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32. Two faces of RUNX3 in myeloid transformation.
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Yokomizo-Nakano T and Sashida G
- Subjects
- Animals, Core Binding Factor Alpha 3 Subunit metabolism, Gene Expression Regulation, Neoplastic, Hematopoiesis, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Myeloid Cells metabolism, Cell Transformation, Neoplastic, Core Binding Factor Alpha 3 Subunit genetics, Leukemia, Myeloid genetics, Myelodysplastic Syndromes genetics, Myeloid Cells pathology
- Abstract
RUNX3, a transcription factor, has been implicated as a tumor suppressor in various cancers, including hematological malignancies; however, recent studies revealed an oncogenic function of RUNX3 in the pathogenesis of myeloid malignancies, such as myelodysplastic syndrome and acute myeloid leukemia. In contrast to the high frequency of mutations in the RUNX1 gene, deletion of and loss-of-function mutations in RUNX3 are rarely detected in patients with hematopoietic malignancies. Although RUNX3 is expressed in normal hematopoietic stem and progenitor cells, its expression decreases with aging in humans. The loss of Runx3 did not result in the development of lethal hematological diseases in mice despite the expansion of myeloid cells. Therefore, RUNX3 does not appear to initiate the transformation of normal hematopoietic stem cells. However, the overexpression of RUNX3 inhibits the expression and transcriptional function of the RUNX1 gene, but activates the expression of key oncogenic pathways, such as MYC, resulting in the transformation of premalignant stem cells harboring a driver genetic mutation. We herein discuss the mechanisms by which RUNX3 is activated and how RUNX3 exerts oncogenic effects on the cellular function of and transcriptional program in premalignant stem cells to drive myeloid transformation., Competing Interests: Conflict of interest disclosure The authors declare that there are no potential conflicts of interest., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
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- 2021
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33. Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms.
- Author
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Daniels NJ, Hershberger CE, Gu X, Schueger C, DiPasquale WM, Brick J, Saunthararajah Y, Maciejewski JP, and Padgett RA
- Subjects
- Base Sequence, Exons, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Introns, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Mutation, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Nuclear Proteins metabolism, RNA, Small Nuclear genetics, RNA, Small Nuclear metabolism, RNA-Binding Proteins metabolism, Ribonucleoprotein, U1 Small Nuclear genetics, Ribonucleoprotein, U1 Small Nuclear metabolism, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Signal Transduction, Spliceosomes, Leukemia, Myeloid genetics, Myelodysplastic Syndromes genetics, Nuclear Proteins genetics, RNA Splicing, RNA-Binding Proteins genetics
- Abstract
Vertebrates have evolved three paralogs, termed LUC7L, LUC7L2, and LUC7L3, of the essential yeast U1 small nuclear RNA (snRNA)-associated splicing factor Luc7p. We investigated the mechanistic and regulatory functions of these putative splicing factors, of which one (LUC7L2) is mutated or deleted in myeloid neoplasms. Protein interaction data show that all three proteins bind similar core but distinct regulatory splicing factors, probably mediated through their divergent arginine-serine-rich domains, which are not present in Luc7p. Knockdown of each factor reveals mostly unique sets of significantly dysregulated alternative splicing events dependent on their binding locations, which are largely non-overlapping. Notably, knockdown of LUC7L2 alone significantly upregulates the expression of multiple spliceosomal factors and downregulates glycolysis genes, possibly contributing to disease pathogenesis. RNA binding studies reveal that LUC7L2 and LUC7L3 crosslink to weak 5' splice sites and to the 5' end of U1 snRNA, establishing an evolutionarily conserved role in 5' splice site selection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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34. The anti-tumour activity of DNA methylation inhibitor 5-aza-2'-deoxycytidine is enhanced by the common analgesic paracetamol through induction of oxidative stress.
- Author
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Gleneadie HJ, Baker AH, Batis N, Bryant J, Jiang Y, Clokie SJH, Mehanna H, Garcia P, Gendoo DMA, Roberts S, Burley M, Molinolo AA, Gutkind JS, Scheven BA, Cooper PR, Parish JL, Khanim FL, and Wiench M
- Subjects
- Acetaminophen pharmacology, Animals, Antimetabolites, Antineoplastic pharmacology, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Decitabine pharmacology, Drug Synergism, HL-60 Cells, Head and Neck Neoplasms metabolism, Humans, Leukemia, Myeloid metabolism, Male, Mice, Reactive Oxygen Species metabolism, Squamous Cell Carcinoma of Head and Neck metabolism, Superoxides metabolism, Xenograft Model Antitumor Assays, Acetaminophen administration & dosage, Antimetabolites, Antineoplastic administration & dosage, Decitabine administration & dosage, Head and Neck Neoplasms drug therapy, Leukemia, Myeloid drug therapy, Oxidative Stress drug effects, Squamous Cell Carcinoma of Head and Neck drug therapy
- Abstract
The DNA demethylating agent 5-aza-2'-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC specifically upregulates cyclooxygenase-2-prostaglandin E
2 pathway, inadvertently providing cancer cells with survival potential, while the addition of paracetamol offsets this effect. Secondly, in the presence of paracetamol, DAC treatment leads to glutathione depletion and finally to accumulation of ROS and/or mitochondrial superoxide, both of which have the potential to restrict tumour growth. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines, further corroborated in a HNSCC xenograft mouse model and through mining of publicly available DAC and paracetamol responses. The sensitizing effect of paracetamol supplementation is specific to DAC but not its analogue 5-azacitidine. In summary, the addition of paracetamol could allow for DAC dose reduction, widening its clinical usability and providing a strong rationale for consideration in cancer therapy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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35. Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential.
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Polomski M, Brachet-Botineau M, Juen L, Viaud-Massuard MC, Gouilleux F, and Prié G
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Molecular Structure, Quinolines chemical synthesis, Quinolines chemistry, STAT5 Transcription Factor metabolism, Signal Transduction drug effects, Structure-Activity Relationship, Tumor Suppressor Proteins metabolism, Antineoplastic Agents pharmacology, Leukemia, Myeloid drug therapy, Quinolines pharmacology, STAT5 Transcription Factor antagonists & inhibitors, Tumor Suppressor Proteins antagonists & inhibitors
- Abstract
Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are two closely related STAT family members that are crucial downstream effectors of tyrosine kinase oncoproteins such as FLT3-ITD in acute myeloid leukemia (AML) and BCR-ABL in chronic myeloid leukemia (CML). We recently developed and reported the synthesis of a first molecule called 17 f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17 f, we synthesized ten analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7 a and 7 a', were identified as having similar or higher antileukemic effects in various AML and CML cell lines. Both molecules were found to be more effective than 17 f at inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML., (© 2020 Wiley-VCH GmbH.)
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- 2021
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36. Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models.
- Author
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Ono R, Masuya M, Inoue N, Shinmei M, Ishii S, Maegawa Y, Maharjan BD, Katayama N, and Nosaka T
- Subjects
- Animals, Hematopoietic Stem Cells metabolism, Mice, Mice, Transgenic, Carcinogenesis genetics, Carcinogenesis metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Gene Expression Regulation, Leukemic, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
The Ten Eleven Translocation 1 (TET1) gene encodes an epigenetic modifying molecule that is involved in demethylation of 5-methylcytosine. In hematological malignancies, loss-of-function mutations of TET2, which is one of the TET family genes including TET1, are frequently found, while the mutations of TET1 are not. However, clinical studies have revealed that TET1 is highly expressed in some cases of the hematological malignancies including acute myeloid leukemia. Indeed, studies by mouse models using conventional Tet1 knockout mice demonstrated that Tet1 is involved in myeloid leukemogenesis by Mixed Lineage Leukemia (MLL) fusion gene or TET2 mutant. Meanwhile, the other study showed that Tet1 is highly expressed in hematopoietic stem cells (HSCs), and that deletion of Tet1 in HSCs enhances potential self-renewal capacity, which is potentially associated with myeloid leukemogenesis. To examine the role of Tet1 in myeloid leukemogenesis more precisely, we generated novel conditional Tet1-knockout mice, which were used to generate the compound mutant mice by crossing with the inducible MLL-ENL transgenic mice that we developed previously. The leukemic immortalization in vitro was not critically affected by conditional ablation of Tet1 in HSCs with the induced expression of MLL-ENL or in hematopoietic progenitor cells retrovirally transduced with MLL-ENL. In addition, the leukemic phenotypes caused by the induced expression of MLL-ENL in vivo was not also critically affected in the compound mutant mouse model by conditional ablation of Tet1, although we found that the expression of Evi1, which is one of critical target genes of MLL fusion gene, in tumor cells was remarkably low under Tet1-ablated condition. These results revealed that Tet1 was dispensable for the myeloid leukemogenesis by MLL-ENL, suggesting that the therapeutic application of Tet1 inhibition may need careful assessment., Competing Interests: Sanikai is Mie University, Faculty of Medicine, School of Medicine, Alumni Association, a non-profit organization. There are no other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2021
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37. Structural Insights into the Interaction of Heme with Protein Tyrosine Kinase JAK2*.
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Schmalohr BF, Mustafa AM, Krämer OH, and Imhof D
- Subjects
- Humans, Leukemia, Myeloid metabolism, Phosphorylation, Protein Conformation, Signal Transduction, Tumor Cells, Cultured, Tyrosine metabolism, Heme chemistry, Heme metabolism, Janus Kinase 2 chemistry, Janus Kinase 2 metabolism, Leukemia, Myeloid pathology, Tyrosine chemistry
- Abstract
Janus kinase 2 (JAK2) is the most important signal-transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal-ion-carrying molecule that is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here, we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 are heme-regulatory motifs and show low-micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein could facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders., (© 2020 The Authors. Published by Wiley-VCH GmbH.)
- Published
- 2021
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38. The application of BH3 mimetics in myeloid leukemias.
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Parry N, Wheadon H, and Copland M
- Subjects
- Animals, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Molecular Targeted Therapy, Proto-Oncogene Proteins c-bcl-2 metabolism, Signal Transduction, Sulfonamides adverse effects, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Drug Design, Leukemia, Myeloid drug therapy, Molecular Mimicry, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides therapeutic use
- Abstract
Execution of the intrinsic apoptotic pathway is controlled by the BCL-2 proteins at the level of the mitochondrial outer membrane (MOM). This family of proteins consists of prosurvival (e.g., BCL-2, MCL-1) and proapoptotic (e.g., BIM, BAD, HRK) members, the functional balance of which dictates the activation of BAX and BAK. Once activated, BAX/BAK form pores in the MOM, resulting in cytochrome c release from the mitochondrial intermembrane space, leading to apoptosome formation, caspase activation, and cleavage of intracellular targets. This pathway is induced by cellular stress including DNA damage, cytokine and growth factor withdrawal, and chemotherapy/drug treatment. A well-documented defense of leukemia cells is to shift the balance of the BCL-2 family in favor of the prosurvival proteins to protect against such intra- and extracellular stimuli. Small molecule inhibitors targeting the prosurvival proteins, named 'BH3 mimetics', have come to the fore in recent years to treat hematological malignancies, both as single agents and in combination with standard-of-care therapies. The most significant example of these is the BCL-2-specific inhibitor venetoclax, given in combination with standard-of-care therapies with great success in AML in clinical trials. As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where we currently stand in this rapidly expanding field is clear.
- Published
- 2021
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39. Regulation of MYB by distal enhancer elements in human myeloid leukemia.
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Li M, Jiang P, Cheng K, Zhang Z, Lan S, Li X, Zhao L, Wang Y, Wang X, Chen J, Ji T, Han B, and Zhang J
- Subjects
- Binding Sites, CCAAT-Enhancer-Binding Protein-beta metabolism, Cell Differentiation, DNA Methylation, Epigenesis, Genetic, GATA1 Transcription Factor metabolism, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-myb metabolism, T-Cell Acute Lymphocytic Leukemia Protein 1 metabolism, U937 Cells, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Leukemia, Myeloid genetics, Proto-Oncogene Proteins c-myb genetics
- Abstract
MYB plays vital roles in regulating proliferation and differentiation of hematopoietic progenitor cells, dysregulation of MYB has been implicated in the pathogenesis of leukemia. Although the transcription of MYB has been well studied, its detailed underlying regulatory mechanisms still remain elusive. Here, we detected the long-range interaction between the upstream regions, -34k and -88k, and the MYB promoter in K562, U937, and HL-60 cells using circularized chromosome conformation capture (4C) assay, which declined when MYB was downregulated during chemical-induced differentiation. The enrichment of enhancer markers, H3K4me1 and H3K27ac, and enhancer activity at the -34k and -88k regions were confirmed by ChIP-qPCR and luciferase assay respectively. ChIP-qPCR showed the dynamic binding of GATA1, TAL1, and CCAAT/enhancer-binding protein (C/EBPβ) at -34k and -88k during differentiation of K562 cells. Epigenome editing by a CRISPR-Cas9-based method showed that H3K27ac at -34k enhanced TF binding and MYB expression, while DNA methylation inhibited MYB expression. Taken together, our data revealed that enhancer elements at -34k are required for MYB expression, TF binding, and epigenetic modification are closely involved in this process in human myeloid leukemia cells.
- Published
- 2021
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40. Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b.
- Author
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Karlsson C, Akula MK, Staffas A, Cisowski J, Sayin VI, Ibrahim MX, Lindahl P, and Bergo MO
- Subjects
- Animals, Antigens, Differentiation genetics, Antigens, Differentiation metabolism, Down-Regulation, Leukemia, Myeloid etiology, Leukemia, Myeloid metabolism, Mice, Mice, Knockout, Antigens, Differentiation chemistry, Endopeptidases physiology, Leukemia, Myeloid pathology
- Published
- 2021
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41. Decitabine Downregulates TIGAR to Induce Apoptosis and Autophagy in Myeloid Leukemia Cells.
- Author
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Li L, Liu W, Sun Q, Zhu H, Hong M, and Qian S
- Subjects
- Apoptosis drug effects, Apoptosis genetics, Apoptosis Regulatory Proteins metabolism, Autophagy drug effects, Autophagy genetics, Down-Regulation drug effects, Down-Regulation genetics, Gene Expression Regulation, Leukemic drug effects, Glycolysis drug effects, Glycolysis genetics, HL-60 Cells, Humans, K562 Cells, Phosphoric Monoester Hydrolases metabolism, Reactive Oxygen Species metabolism, Apoptosis Regulatory Proteins genetics, Decitabine pharmacology, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Phosphoric Monoester Hydrolases genetics
- Abstract
Decitabine (DAC) is a well-known DNA methyltransferase inhibitor, which has been widely used for the treatment of acute myeloid leukemia (AML). However, in addition to hypomethylation, DAC in AML is also involved in cell metabolism, apoptosis, and immunity. The TP53-induced glycolysis and apoptosis regulator (TIGAR) functions to inhabit glycolysis and protect cancer cells from reactive oxygen species- (ROS-) associated apoptosis. Our previous study revealed that TIGAR is highly expressed in myeloid leukemia cell lines and AML primary cells and associated with poor prognosis in adult patients with cytogenetically normal AML. In the present study, it was found that in a time- and concentration-dependent manner, DAC downregulates the TIGAR expression, induces ROS production, and promotes apoptosis in HL-60 and K562 cells. However, blocking the glycolytic pathway partially reversed the combined effects of DAC and TIGAR knockdown on apoptosis, ROS production, and cell cycle arrest, indicating that DAC induced apoptosis through the glycolytic pathway. Furthermore, TIGAR also has a negative impact on autophagy, while DAC treatment upregulates autophagy-related proteins LC3, Beclin-1, ATG3, and ATG-5, downregulates p62, and promotes the formation of autophagosomes, indicating that DAC may activate autophagy by downregulating TIGAR. Taken together, DAC plays an unmethylated role in inducing apoptosis and activating autophagy in myeloid leukemia by downregulating TIGAR., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Lanzhu Li et al.)
- Published
- 2021
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42. BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia.
- Author
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Ramsey HE, Greenwood D, Zhang S, Childress M, Arrate MP, Gorska AE, Fuller L, Zhao Y, Stengel K, Fischer MA, Stubbs MC, Liu PCC, Boyd K, Rathmell JC, Hiebert SW, and Savona MR
- Subjects
- Acute Disease, Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis genetics, Cell Cycle drug effects, Cell Cycle genetics, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Dose-Response Relationship, Drug, Drug Synergism, Female, Gene Expression Regulation, Leukemic drug effects, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Proteins metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Mice, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Leukemia, Myeloid drug therapy, Organic Chemicals pharmacology, Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides pharmacology
- Abstract
Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity., Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models., Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2 , and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity., Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen., (©2020 American Association for Cancer Research.)
- Published
- 2021
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43. A Real-Time, Bioluminescent Apoptosis Assay.
- Author
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Kupcho KR and Niles AL
- Subjects
- Breast Neoplasms metabolism, Female, Humans, Leukemia, Myeloid metabolism, Tumor Cells, Cultured, Annexin A5 metabolism, Apoptosis, Breast Neoplasms pathology, Flow Cytometry methods, Leukemia, Myeloid pathology, Luminescent Measurements methods
- Abstract
This chapter describes a real-time, bioluminescent apoptosis assay technique, which circumvents the well-documented "timing condundrum" encountered when employing traditional apoptosis detection chemistries after exposures with inducers of unknown potential. The assay continuously reports the translocation of phosphatidylserine (PS) from the inner membrane leaflet of a cell to the exofacial surface during apoptosis. This homogenous, no-wash, plate-based assay is made possible by two different annexin V fusion proteins, which contain complementing NanoBiT™ luciferase enzyme subunits, a time-released luciferase substrate, and a fluorescent membrane integrity reagent. During apoptosis, luminescence signal is proportional to PS exposure and fluorescence intensity correlated with the degree of secondary necrosis. Altogether, the measures provide exquisite kinetic resolution of dose- and agent-dependent apoptotic responses, from early through late phases. At exposure termination, other compatible reagents can be applied to measure additional orthogonal correlates of cell health.
- Published
- 2021
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44. LncRNA CCDC26 Interacts with CELF2 Protein to Enhance Myeloid Leukemia Cell Proliferation and Invasion via the circRNA_ANKIB1/miR-195-5p/PRR11 Axis.
- Author
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Li C, Mu J, Shi Y, and Xin H
- Subjects
- Cell Proliferation physiology, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Neoplasm Invasiveness, Transfection, CELF Proteins metabolism, Leukemia, Myeloid metabolism, MicroRNAs metabolism, Nerve Tissue Proteins metabolism, Proteins metabolism, RNA, Circular metabolism, RNA, Long Noncoding metabolism
- Abstract
LncRNA CCDC26 is aberrantly expressed in myeloid leukemia (ML) and promotes myeloid leukemia progression, but the potential mechanism of CCDC26 in regulating ML progression is unclear. In this study, we observed that lncRNA CCDC26 was upregulated in both chronic and acute ML cell lines. LncRNA CCDC26 promoted the proliferation and invasion of K562 and HL-60 cells, which was determined by cell counting kit-8 test and Transwell invasion assay. Flow cytometry showed that lncRNA CCDC26 inhibited cell apoptosis. Bioinformatics and expression correlation analyses revealed that there was a potential interaction between CCDC26 and CUGBP Elav-like family member 2 (CELF2) protein, an RNA bind protein (RBP). Then the relationship between CCDC26 and the RBP CELF2 was identified by using RNA pull-down and RNA immunoprecipitation (RNA-IP) assays. Further analysis showed that overexpression of CCDC26 could noticeably upregulate circRNA_ANKIB1 expression via sponging CELF2. Subsequently, we found that overexpressed circRNA_ANKIB1 could significantly promote proline rich 11 (PRR11) protein expression by sponging miR-195a-5p. Moreover, PRR11 was also upregulated by CCDC26 and downregulated by CELF2. Mechanically, we uncovered that the miR-195a-5p inhibitor activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways through upregulating PRR11 protein expression. Furthermore, the inhibitors of AKT, p65-NF-κB, or Bcl-2 could inhibit the effect of the miR-195a-5p inhibitor on ML cell behaviors. In conclusion, lncRNA CCDC26 could upregulate PRR11 protein expression by sponging miR-195a-5p, thereby activating the PI3K/AKT and NF-κB pathways to enhance ML cell proliferation and invasion and suppress cell apoptosis.
- Published
- 2021
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45. Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation.
- Author
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Perner F and Armstrong SA
- Subjects
- Acetylation, Animals, DNA Methylation, Epigenesis, Genetic, Histone Code, Histone Demethylases metabolism, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Humans, Models, Biological, Myeloid-Lymphoid Leukemia Protein metabolism, Protein Domains, Protein Interaction Mapping, Proto-Oncogene Proteins metabolism, Transcription, Genetic, Chromatin metabolism, Gene Expression Regulation, Leukemic, Leukemia, Myeloid metabolism
- Abstract
The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein-protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials.
- Published
- 2020
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46. Elephantopus mollis Kunth extracts induce antiproliferation and apoptosis in human lung cancer and myeloid leukemia cells.
- Author
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Bich Ngoc TT, Hoai Nga NT, My Trinh NT, Thuoc TL, and Phuong Thao DT
- Subjects
- A549 Cells, Animals, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis physiology, Burkitt Lymphoma drug therapy, Burkitt Lymphoma metabolism, Cell Proliferation drug effects, Cell Proliferation physiology, HL-60 Cells, Humans, Leukemia, Myeloid drug therapy, Lung Neoplasms drug therapy, Mice, NIH 3T3 Cells, Plant Extracts isolation & purification, Plant Extracts pharmacology, Antineoplastic Agents, Phytogenic therapeutic use, Apoptosis drug effects, Asteraceae, Leukemia, Myeloid metabolism, Lung Neoplasms metabolism, Plant Extracts therapeutic use
- Abstract
Ethnopharmacological Relevance: Elephantopus mollis Kunth (EM), which belongs to Asteraceae family, has been used as a folk medicine with diverse therapeutic properties. Previous studies reported that crude extracts of this plant could inhibit several cancer cell lines, including breast carcinoma MCF-7, liver carcinoma HepG2, colorectal carcinoma DLD-1, lung carcinoma NCI-H23, etc. AIM: In this study, the anticancer activity and associated molecular mechanism of EM which is distributed in Vietnam were investigated., Materials and Methods: The cytotoxicity of various EM extracts was evaluated on different cell lines by MTT assay. In addition, the effects of EM extracts on cell growth, cell morphology, nuclear morphology, caspase-3 activation, and mRNA expression levels of apoptosis-related genes were also examined., Results: Our results demonstrated that ethyl acetate extract (EM-EA) caused proliferative inhibition and apoptotic induction towards A549 lung cancer cells (IC
50 = 18.66 μg/ml, SI = 5.8) and HL60 leukemia cells (IC50 = 7.45 μg/ml, SI = 14.5) while petroleum ether extract (EM-PE) showed high toxicity to HL60 cell line (IC50 = 11.14 μg/ml, SI = 6.7). Notably, Raji lymphoma cells were also affected by these extracts (IC50 < 20 μg/ml, SI > 4), which has not been reported yet. Furthermore, mechanisms of EM extracts were elucidated. The significant downregulation of PCNA mRNA level induced by EM-EA/PE extracts contributed to the cell-growth restraint. EM-EA extract might activate apoptosis in A549 cells through both extrinsic and intrinsic signaling pathways by causing a 1.55-fold increase in BID, 3.65-fold increase in BAK and 3.11-fold decrease in BCL-2 expression level. Meanwhile, with EM-EA-extract treatment, HL60 cells might encounter P53-dependent apoptotic deaths., Conclusions: The combination of antiproliferation and apoptosis activation contributed to the high efficacy of EM extracts. These findings not only proved the anticancer potential of EM but also provided further insights into the mechanisms of EM extracts., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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47. Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells.
- Author
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Tremblay CS, Chiu SK, Saw J, McCalmont H, Litalien V, Boyle J, Sonderegger SE, Chau N, Evans K, Cerruti L, Salmon JM, McCluskey A, Lock RB, Robinson PJ, Jane SM, and Curtis DJ
- Subjects
- Acute Disease, Animals, Cell Line, Tumor, Dynamins metabolism, Humans, Leukemia, Myeloid metabolism, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mice, Transgenic, Neoplastic Stem Cells drug effects, Stem Cell Niche drug effects, Tumor Microenvironment drug effects, Cyanoacrylates pharmacology, Dynamins antagonists & inhibitors, Endocytosis drug effects, Indoles pharmacology, Leukemia, Myeloid drug therapy, Xenograft Model Antitumor Assays methods
- Abstract
Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.
- Published
- 2020
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48. ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine.
- Author
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Fontana D, Mauri M, Renso R, Docci M, Crespiatico I, Røst LM, Jang M, Niro A, D'Aliberti D, Massimino L, Bertagna M, Zambrotta G, Bossi M, Citterio S, Crescenzi B, Fanelli F, Cassina V, Corti R, Salerno D, Nardo L, Chinello C, Mantegazza F, Mecucci C, Magni F, Cavaletti G, Bruheim P, Rea D, Larsen S, Gambacorti-Passerini C, and Piazza R
- Subjects
- Cell Line, Cell Respiration drug effects, Cell Respiration genetics, DNA Breaks drug effects, Electron Transport Complex II drug effects, Electron Transport Complex II metabolism, Ethanolamines metabolism, Humans, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Mitochondria genetics, Mitochondria pathology, Mutation, Phenotype, Phosphotransferases (Alcohol Group Acceptor) metabolism, Reactive Oxygen Species metabolism, Succinic Acid metabolism, Tigecycline pharmacology, Ethanolamines pharmacology, Mitochondria drug effects, Mitochondria metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics
- Abstract
Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
- Published
- 2020
- Full Text
- View/download PDF
49. Effects of Cedrus atlantica extract on acute myeloid leukemia cell cycle distribution and apoptosis.
- Author
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Hung PH, Hsieh MC, Lee SC, Huang XF, Chang KF, Chen SY, Lee MS, and Tsai NM
- Subjects
- Acute Disease, Animals, Caspases metabolism, Cell Line, Tumor, Cell Survival drug effects, HL-60 Cells, Humans, Jurkat Cells, K562 Cells, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Mice, RAW 264.7 Cells, Vascular Endothelial Growth Factor A metabolism, Apoptosis drug effects, Cedrus chemistry, Cell Cycle drug effects, Plant Extracts pharmacology
- Abstract
This study investigated the anti-leukemic effects of Cedrus atlantica extract (CAt extract) on cell cycle distribution and apoptosis in human acute myeloid leukemia (AML) cells. AML often occurs in older adults, accounting for 60% of the cases, and is likely to be resistant to chemotherapy due to multidrug resistance, resulting in early death during cancer treatment. With the increasing focus on prevention medicine, natural plant components are being used as a major source for the development of therapeutic drugs or functional foods to cure or alleviate the disease. Cedrus species are known to have anti-inflammatory, antimicrobial, antiviral, and anticancer effects; however, the anticancer effects of CAt extract have not been elucidated. In this study, CAt extract demonstrated an inhibitory effect on human leukemia cells in a concentration-dependent manner; CAt extract induced G
0 /G1 phase arrest via restrained protein levels of p-Rb and cell cycle-related proteins. After CAt extract exposure, the extrinsic and intrinsic apoptotic pathways were activated through caspase-8, -9, and -3 cleavage. Additionally, CAt extract suppressed VEGF, MMP-2, and MMP-9 expression. This study demonstrated that CAt extract treatment significantly reduced cell growth, cell cycle arrest in the G0 /G1 phase, and induction of apoptosis, leading to leukemia cell death.- Published
- 2020
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50. Effect of methoxy stilbenes-analogs of resveratrol-on the viability and induction of cell cycle arrest and apoptosis in human myeloid leukemia cells.
- Author
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Zielińska-Przyjemska M, Kaczmarek M, Krajka-Kuźniak V, Wierzchowski M, and Baer-Dubowska W
- Subjects
- Antioxidants pharmacology, Cell Survival, Gene Expression Regulation, Neoplastic, HL-60 Cells, Humans, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Tumor Suppressor Protein p53 metabolism, bcl-2-Associated X Protein metabolism, bcl-X Protein metabolism, Apoptosis, Cell Cycle Checkpoints, Leukemia, Myeloid drug therapy, Resveratrol analogs & derivatives, Resveratrol pharmacology, Stilbenes chemistry
- Abstract
The present study aimed to evaluate the cytotoxicity and its mechanism of five synthetic methoxy stilbenes, namely 3,4,4'-trimethoxy, 3,4,2'-trimethoxy, 3,4,2',4'-tetramethoxy, 3,4,2',6'-tetramethoxy, and 3,4,2',4',6'-pentamethoxy-trans-stilbenes (MS), in comparison with resveratrol (RSV). Human promyelocytic (HL-60) and monocytic leukemia (THP-1) cells were treated with the tested compounds for 24 h, and cytotoxicity, cell cycle distribution, and apoptosis were evaluated. Significant differences were found in the susceptibility of these cell lines to all stilbenes, including RSV. The THP-1 cells were more resistant to cytotoxic activity of these compounds than HL-60 cells. Among the tested stilbenes, 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS exhibited higher cytotoxicity toward both cell lines than RSV and the other methoxy stilbenes. This activity might be related to cell cycle arrest at the G2/M phase and induction of apoptosis. In this regard, 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS at highest concentrations increased the p53 protein level particularly in HL-60 cells. Moreover, treatment with these derivatives increased the ratio of the proapoptotic Bax protein to the antiapoptotic Bcl-xl protein, suggesting the induction of apoptosis through the intrinsic mitochondrial pathway in both cell lines. Further studies are required to fully elucidate the mechanism of these activities.
- Published
- 2020
- Full Text
- View/download PDF
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