38 results on '"Ganan-Gomez I"'
Search Results
2. IS06 - SINGLE CELL DATA
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Ganan-Gomez, I., Chien, K., Adema, V., Ma, F., Yang, H., Montalban-Bravo, G., Rodriguez-Sevilla, J., Tan, L., Lorenzi, P., Clise-Dwyer, K., Garcia-Manero, G., and Colla, S.
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- 2023
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3. S160: MOLECULAR DETERMINANTS OF DISEASE PROGRESSION AFTER HYPOMETHYLATING AGENT THERAPY IN RAS PATHWAY MUTANT CHRONIC MYELOMONOCYTIC LEUKEMIA AT THE SINGLE-CELL LEVEL
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Montalban-Bravo, G., primary, Ma, F., additional, Ganan-Gomez, I., additional, Kanagal-Shamana, R., additional, Adema, V., additional, Thongon, N., additional, Yang, H., additional, Soltysiak, K. A., additional, Bueso-Ramos, C., additional, Kantarjian, H., additional, Garcia-Manero, G., additional, and Colla, S., additional
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- 2022
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4. O04 - Topic: AS04-MDS Biology and Pathogenesis/AS04d-Somatic mutations: SINGLE-CELL-LEVEL ANALYSIS OF SF3B1-MUTANT MYELODYSPLASTIC SYNDROME WITH RINGED SIDEROBLASTS
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Adema, V., Kanagal-Shamanna, R., Ma, F., Yang, H., Ganan-Gomez, I., Santoni, A., Thongon, N., Montalban-Bravo, G., Pellegrini, M., Bueso-Ramos, C., Maciejewski, J., Visconte, V., Carew, J., Garcia-Manero, G., and Colla, S.
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- 2021
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5. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells
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Wei, Y, Chen, R, Dimicoli, S, Bueso-Ramos, C, Neuberg, D, Pierce, S, Wang, H, Yang, H, Jia, Y, Zheng, H, Fang, Z, Nguyen, M, Ganan-Gomez, I, Ebert, B, Levine, R, Kantarjian, H, and Garcia-Manero, G
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- 2013
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6. Topic: AS04-MDS Biology and Pathogenesis/AS04d-Somatic mutations
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Adema, V., primary, Kanagal-Shamanna, R., additional, Ma, F., additional, Yang, H., additional, Ganan-Gomez, I., additional, Santoni, A., additional, Thongon, N., additional, Montalban-Bravo, G., additional, Pellegrini, M., additional, Bueso-Ramos, C., additional, Maciejewski, J., additional, Visconte, V., additional, Carew, J., additional, Garcia-Manero, G., additional, and Colla, S., additional
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- 2021
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7. Toll-like receptor alterations in myelodysplastic syndrome
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Wei, Y, Dimicoli, S, Bueso-Ramos, C, Chen, R, Yang, H, Neuberg, D, Pierce, S, Jia, Y, Zheng, H, Wang, H, Wang, X, Nguyen, M, Wang, S A, Ebert, B, Bejar, R, Levine, R, Abdel-Wahab, O, Kleppe, M, Ganan-Gomez, I, Kantarjian, H, and Garcia-Manero, G
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- 2013
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8. PS1325 IDENTIFICATION AND TARGETING OF MOLECULAR SIGNATURES OF HYPOMETHYLATING AGENT RESISTANCE IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA
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Wei, Y., primary, Class, C., additional, Kanagal-Shamanna, R., additional, Zheng, H., additional, Estecio, M., additional, Lu, Y., additional, Soltysiak, K., additional, Yang, H., additional, Sasaki, K., additional, Montalban-Bravo, G., additional, Ganan-Gomez, I., additional, Do, K.-A., additional, Colla, S., additional, Bueso-Ramos, C., additional, and Garcia-Manero, G., additional
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- 2019
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9. 52 - Identification of the Specific Hematopoietic Stem Cell Populations Responsible for Failure to Hypomethylating Agents in Myelodysplastic Syndromes
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Ganan-Gomez, I., Alfonso, A., Ogoti, Y., Yang, H., Montalban-Bravo, G., Yu, A.C., Silver, S., Clise-Dwyer, K., Garcia-Manero, G., and Colla, S.
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- 2017
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10. Identification of the Specific Hematopoietic Stem Cell Populations Responsible for Failure to Hypomethylating Agents in Myelodysplastic Syndromes
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Ganan-Gomez, I., primary, Alfonso, A., additional, Ogoti, Y., additional, Yang, H., additional, Montalban-Bravo, G., additional, Yu, A.C., additional, Silver, S., additional, Clise-Dwyer, K., additional, Garcia-Manero, G., additional, and Colla, S., additional
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- 2017
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11. Dequalinium inhibits autophagy in the human leukemic cell line NB4: apoptosis resistance mechanism or cell death inducer?
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Estan-Omana, M. C., Ganan-Gomez, I., Makowska, K. A., Moreno-Cubero, E., Sancho, P., Rubio, V., José C. Diez, and Boyano-Adanez, M. D. C.
12. Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia.
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Montalban-Bravo G, Thongon N, Rodriguez-Sevilla JJ, Ma F, Ganan-Gomez I, Yang H, Kim YJ, Adema V, Wildeman B, Tanaka T, Darbaniyan F, Al-Atrash G, Dwyer K, Loghavi S, Kanagal-Shamanna R, Song X, Zhang J, Takahashi K, Kantarjian H, Garcia-Manero G, and Colla S
- Subjects
- Humans, Animals, Mice, Signal Transduction drug effects, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells drug effects, Disease Progression, Sulfonamides pharmacology, Sulfonamides therapeutic use, NF-kappa B metabolism, DNA Methylation drug effects, DNA Methylation genetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Blast Crisis pathology, Blast Crisis drug therapy, Blast Crisis genetics, Blast Crisis metabolism, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic pathology, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic metabolism, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Myeloid Cell Leukemia Sequence 1 Protein genetics, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Apoptosis drug effects, Mutation genetics
- Abstract
RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML., Competing Interests: Declaration of interests G.M.-B. declares research support from Rigel Pharmaceuticals, IFM Therapeutics, and Takeda Oncology. K.T. declares support from Symbio Pharmaceuticals, Novartis, Celgene/BMS, and GSK, and honoraria from Mission Bio and Illumina. H.K. declares research support from and an advisory role at Actinium and research support from AbbVie, Agio, Amgen, Ariad, Astex, Bristol Myers Squibb, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. G.G-M. declares research support from and an advisory role at Bristol Myers Squibb, Astex, and Helsinn, and research support from Amphivena, Novartis, AbbVie, H3 Biomedicine, Onconova, and Merck. S.C. declares research support from Amgen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.
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Bazinet A, Desikan SP, Li Z, Rodriguez-Sevilla JJ, Venugopal S, Urrutia S, Montalban-Bravo G, Sasaki K, Chien KS, Hammond D, Kanagal-Shamanna R, Ganan-Gomez I, Kadia TM, Borthakur G, DiNardo CD, Daver NG, Jabbour EJ, Ravandi F, Kantarjian H, and Garcia-Manero G
- Subjects
- Humans, Prospective Studies, DNA Methylation, Cytogenetic Analysis, Retrospective Studies, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic
- Abstract
Purpose: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood., Experimental Design: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes., Results: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes., Conclusions: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax., (©2024 American Association for Cancer Research.)
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- 2024
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14. Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.
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Rodriguez-Sevilla JJ, Ganan-Gomez I, Ma F, Chien K, Del Rey M, Loghavi S, Montalban-Bravo G, Adema V, Wildeman B, Kanagal-Shamanna R, Bazinet A, Chifotides HT, Thongon N, Calvo X, Hernández-Rivas JM, Díez-Campelo M, Garcia-Manero G, and Colla S
- Subjects
- Humans, Hematopoietic Stem Cells metabolism, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic metabolism, Sulfonamides pharmacology, Sulfonamides therapeutic use, Sulfonamides metabolism, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax., (© 2024. The Author(s).)
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- 2024
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15. Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.
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Thongon N, Ma F, Baran N, Lockyer P, Liu J, Jackson C, Rose A, Furudate K, Wildeman B, Marchesini M, Marchica V, Storti P, Todaro G, Ganan-Gomez I, Adema V, Rodriguez-Sevilla JJ, Qing Y, Ha MJ, Fonseca R, Stein C, Class C, Tan L, Attanasio S, Garcia-Manero G, Giuliani N, Berrios Nolasco D, Santoni A, Cerchione C, Bueso-Ramos C, Konopleva M, Lorenzi P, Takahashi K, Manasanch E, Sammarelli G, Kanagal-Shamanna R, Viale A, Chesi M, and Colla S
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- Humans, DNA Helicases metabolism, Metabolic Reprogramming, DNA Repair, DNA Damage, Multiple Myeloma genetics
- Abstract
DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation., (© 2024. The Author(s).)
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- 2024
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16. IL-1β-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes.
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Adema V, Ganan-Gomez I, Ma F, Rodriguez-Sevilla JJ, Chien K, Yang H, Thongon N, Kanagal-Shamanna R, Loghavi S, Montalban-Bravo G, Hammond D, Gu Y, Tan R, Tan L, Lorenzi P, Al-Atrash G, Clise-Dwyer K, Bejar R, Pellegrini M, Garcia-Manero G, and Colla S
- Abstract
Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.
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- 2023
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17. Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.
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Thongon N, Ma F, Lockyer P, Baran N, Liu J, Jackson C, Rose A, Wildeman B, Marchesini M, Marchica V, Storti P, Giuliani N, Ganan-Gomez I, Adema V, Qing Y, Ha M, Fonseca R, Class C, Tan L, Kanagal-Shamanna R, Nolasco DB, Cerchione C, Montalban-Bravo G, Santoni A, Bueso-Ramos C, Konopleva M, Lorenzi P, Garcia-Manero G, Manasanch E, Viale A, Chesi M, and Colla S
- Abstract
DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation., Statement of Significance: Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.
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- 2023
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18. Isolation, culture, and immunophenotypic analysis of bone marrow HSPCs from patients with myelodysplastic syndromes.
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Ganan-Gomez I, Clise-Dwyer K, and Colla S
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- Humans, Hematopoietic Stem Cells, Stromal Cells, Bone Marrow Cells, Bone Marrow, Myelodysplastic Syndromes
- Abstract
Drug testing assays in hematopoietic stem and progenitor cells (HSPCs) are fundamental in biological studies of myelodysplastic syndromes (MDS) but have historically entailed a technical challenge. This protocol allows the efficient isolation of MDS HSPCs from bone marrow mononuclear cell fractions and their culturing with the support of stromal cells for improved maintenance during drug testing. Lastly, specific steps are given to quantify surviving cells and assess changes in the HSPC hierarchies. For complete details on the use and execution of this protocol, please refer to Ganan-Gomez et al. (2022)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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19. MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.
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Wei Y, Zheng H, Lockyer PP, Darbaniyan F, Li Z, Kanagal-Shamanna R, Soltysiak KA, Yang H, Ganan-Gomez I, Montalban-Bravo G, Chien KS, Do KA, Daver N, and Garcia-Manero G
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- Animals, Mice, Azacitidine pharmacology, Azacitidine therapeutic use, Imidazoles therapeutic use, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2 -knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.
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- 2022
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20. Transcriptomic Signatures of Hypomethylating Agent Failure in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia.
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Darbaniyan F, Zheng H, Kanagal-Shamanna R, Lockyer P, Montalban-Bravo G, Estecio M, Lu Y, Soltysiak KA, Chien KS, Yang H, Sasaki K, Class C, Ganan-Gomez I, Do KA, Garcia-Manero G, and Wei Y
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- Humans, Mice, Animals, Transcriptome, Azacitidine pharmacology, Azacitidine therapeutic use, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes metabolism, Leukemia, Myelomonocytic, Juvenile drug therapy
- Abstract
Hypomethylating agents (HMAs) are the standard of care for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). HMA treatment failure is a major clinical problem and its mechanisms are poorly characterized. We performed RNA sequencing in CD34
+ bone marrow stem hematopoietic stem and progenitor cells (BM-HSPCs) from 51 patients with CMML and MDS before HMA treatment and compared transcriptomic signatures between responders and nonresponders. We observed very few genes with significant differential expression in HMA non-responders versus responders, and the commonly altered genes in non-responders to both azacitidine (AZA) and decitabine (DAC) treatments were immunoglobulin genes. Gene set analysis identified 78 biological pathways commonly altered in non-responders to both treatments. Among these, we determined that the γ-aminobutyric acid (GABA) receptor signaling significantly affected hematopoiesis in both human BM-HSPCs and mice, indicating that the transcriptomic signatures identified here could serve as candidate biomarkers and therapeutic targets for HMA failure in MDS and CMML., Competing Interests: Conflict of Interest Disclosure The authors declare no competing interests., (Published by Elsevier Inc.)- Published
- 2022
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21. A machine learning-based method for automatically identifying novel cells in annotating single-cell RNA-seq data.
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Li Z, Wang Y, Ganan-Gomez I, Colla S, and Do KA
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- Sequence Analysis, RNA methods, RNA-Seq, Software, Machine Learning, Single-Cell Analysis methods, Gene Expression Profiling methods
- Abstract
Motivation: Single-cell RNA sequencing (scRNA-seq) has been widely used to decompose complex tissues into functionally distinct cell types. The first and usually the most important step of scRNA-seq data analysis is to accurately annotate the cell labels. In recent years, many supervised annotation methods have been developed and shown to be more convenient and accurate than unsupervised cell clustering. One challenge faced by all the supervised annotation methods is the identification of the novel cell type, which is defined as the cell type that is not present in the training data, only exists in the testing data. Existing methods usually label the cells simply based on the correlation coefficients or confidence scores, which sometimes results in an excessive number of unlabeled cells., Results: We developed a straightforward yet effective method combining autoencoder with iterative feature selection to automatically identify novel cells from scRNA-seq data. Our method trains an autoencoder with the labeled training data and applies the autoencoder to the testing data to obtain reconstruction errors. By iteratively selecting features that demonstrate a bi-modal pattern and reclustering the cells using the selected feature, our method can accurately identify novel cells that are not present in the training data. We further combined this approach with a support vector machine to provide a complete solution for annotating the full range of cell types. Extensive numerical experiments using five real scRNA-seq datasets demonstrated favorable performance of the proposed method over existing methods serving similar purposes., Availability and Implementation: Our R software package CAMLU is publicly available through the Zenodo repository (https://doi.org/10.5281/zenodo.7054422) or GitHub repository (https://github.com/ziyili20/CAMLU)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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22. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study.
- Author
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Bazinet A, Darbaniyan F, Jabbour E, Montalban-Bravo G, Ohanian M, Chien K, Kadia T, Takahashi K, Masarova L, Short N, Alvarado Y, Yilmaz M, Ravandi F, Andreeff M, Kanagal-Shamanna R, Ganan-Gomez I, Colla S, Qiao W, Huang X, McCue D, Mirabella B, Kantarjian H, and Garcia-Manero G
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Azacitidine adverse effects, Bridged Bicyclo Compounds, Heterocyclic, Female, Humans, Male, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myelomonocytic, Chronic drug therapy, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes etiology
- Abstract
Background: Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for treatment-naive and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia., Methods: We did a single centre, dose-escalation, dose-expansion, phase 1-2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was used. Patients were treated with intravenous or subcutaneous azacitidine (75 mg/m
2 ) for 5 days and oral venetoclax (100-400 mg) for 7-14 days. The primary outcome was safety and tolerability as well as determination of the maximum tolerated dose and recommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3 study design. All patients who received one dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT04160052. The phase 2 dose-expansion part of the trial is ongoing., Findings: Between Nov 12, 2019, and Dec 17, 2021, a total of 23 patients were enrolled in the phase 1 portion of this study (17 [74%] hypomethylating agent naive and six [26%] post-hypomethylating agent failure). 18 (78%) patients were male and five (22%) were female; 21 (91%) were white and two (9%) were Asian. Median follow-up was 13·2 months (IQR 6·8-18·3). The maximum tolerated dose was not reached and the recommended phase 2 dose was established as azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days. The most common grade 3-4 treatment-emergent adverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]), lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths due to sepsis, which were not deemed treatment-related, occurred on the study drugs. The overall response rate was 87% (95% CI 66-97; 20 of 23 patients)., Interpretation: Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia., Funding: MD Anderson Cancer Center., Competing Interests: Declaration of interests EJ declares research funding from Amgen, Pfizer, Abbvie, Adaptive Biotechnologies, Astex, and Ascentage; and consulting fees from Amgen, Pfizer, Abbvie, Takeda, Adaptive Biotechnologies, Astex, Ascentage, Genentech, Novartis, BMS, Jazz Pharmaceuticals, Hikma Pharmaceuticals, and Incyte. GM-B declares research funding from IFM Therapeutics, Rigel Pharmaceuticals, Jazz Pharmaceuticals, Daiichi Sankyo, Stemline Therapeutics, and Salarius Pharmaceuticals. TK reports research funding from Ascentage and Abbvie; and consulting fees from Abbvie. KT reports consulting fees from SymBio Pharmaceuticals, Novartis, Celgene/BMS, GSK, and Agios; and payment or honoraria from Otsuka Pharmaceutical, Mission Bio, and Illumina. NS reports research funding from Astellas Pharma, Stemline Therapeutics, Xencor, and Takeda Oncology; consulting fees from Pfizer and Jazz Pharmaceuticals; and payment or honoraria from Pfizer, Novartis, Astellas Pharma, and Amgen. MY reports research funding from Pfizer and Daiichi Sankyo. MA declares research funding from Daiichi Sankyo, Breast Cancer Research Foundation, AstraZeneca, Oxford Biomedical UK, Brooklyn ITX, SentiBio, Pinot Bio, and Syndax; participation on a data monitoring or advisory board with Cancer UK, Leukemia & Lymphoma Society, Aptose, German Research Council, NCI, CLL Foundation, Brooklyn ITX; and stock or stock options with Reata, Aptose, Eutropics, SentiBio, and Chimerix. HK declares research funding from Abbvie, Amgen, Ascentage, BMS, Daiichi Sankyo, Immunogen, Jazz Pharmaceuticals, Novartis; and payment or honoraria from Abbvie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Precision Biosciences, Shenzhen Target Rx, and Takeda. GG-M declares research funding from Astex Pharmaceuticals, Novartis, Abbvie, BMS, Genentech, Aprea Therapeutics, Curis, Gilead Sciences; consulting fees from Astex Pharmaceuticals, Acceleron Pharma, and BMS; and payment or honoraria from Astex Pharmaceuticals, Acceleron Pharma, Abbvie, Novartis, Gilead Sciences, Curis, Genentech, and BMS. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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23. Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia.
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Wei Y, Kanagal-Shamanna R, Zheng H, Bao N, Lockyer PP, Class CA, Darbaniyan F, Lu Y, Lin K, Yang H, Montalban-Bravo G, Ganan-Gomez I, Soltysiak KA, Do KA, Colla S, and Garcia-Manero G
- Subjects
- Animals, Gene Expression Profiling, Genome, Humans, Loss of Function Mutation, Mice, Mutation, Proto-Oncogene Proteins genetics, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dioxygenases deficiency, Dioxygenases genetics, Dioxygenases metabolism, Jumonji Domain-Containing Histone Demethylases biosynthesis, Jumonji Domain-Containing Histone Demethylases genetics, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic metabolism, Leukemia, Myelomonocytic, Juvenile genetics, Leukemia, Myelomonocytic, Juvenile metabolism
- Abstract
Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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24. Author Correction: Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy.
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Ganan-Gomez I, Yang H, Ma F, Montalban-Bravo G, Thongon N, Marchica V, Richard-Carpentier G, Chien K, Manyam G, Wang F, Alfonso A, Chen S, Class C, Kanagal-Shamanna R, Ingram JP, Ogoti Y, Rose A, Loghavi S, Lockyer P, Cambo B, Muftuoglu M, Schneider S, Adema V, McLellan M, Garza J, Marchesini M, Giuliani N, Pellegrini M, Wang J, Walker J, Li Z, Takahashi K, Leverson JD, Bueso-Ramos C, Andreeff M, Clise-Dwyer K, Garcia-Manero G, and Colla S
- Published
- 2022
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25. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy.
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Ganan-Gomez I, Yang H, Ma F, Montalban-Bravo G, Thongon N, Marchica V, Richard-Carpentier G, Chien K, Manyam G, Wang F, Alfonso A, Chen S, Class C, Kanagal-Shamanna R, Ingram JP, Ogoti Y, Rose A, Loghavi S, Lockyer P, Cambo B, Muftuoglu M, Schneider S, Adema V, McLellan M, Garza J, Marchesini M, Giuliani N, Pellegrini M, Wang J, Walker J, Li Z, Takahashi K, Leverson JD, Bueso-Ramos C, Andreeff M, Clise-Dwyer K, Garcia-Manero G, and Colla S
- Subjects
- Hematopoietic Stem Cells pathology, Humans, Proto-Oncogene Proteins c-bcl-2 genetics, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology
- Abstract
Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS., (© 2022. The Author(s).)
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- 2022
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26. Hematopoiesis under telomere attrition at the single-cell resolution.
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Thongon N, Ma F, Santoni A, Marchesini M, Fiorini E, Rose A, Adema V, Ganan-Gomez I, Groarke EM, Gutierrez-Rodrigues F, Chen S, Lockyer P, Schneider S, Bueso-Ramos C, Montalban-Bravo G, Class CA, Soltysiak KA, Pellegrini M, Sahin E, Bertuch AA, DiNardo CD, Garcia-Manero G, Young NS, Dwyer K, and Colla S
- Subjects
- Animals, Bone Marrow Failure Disorders genetics, Bone Marrow Failure Disorders metabolism, Bone Marrow Failure Disorders pathology, Cell Self Renewal, Cellular Reprogramming, Hematopoiesis genetics, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Interferons metabolism, Megakaryocytes cytology, Megakaryocytes metabolism, Mice, Nuclear Proteins metabolism, Oligodeoxyribonucleotides metabolism, Phosphoproteins metabolism, Signal Transduction, Single-Cell Analysis, Telomere chemistry, Telomere physiology, Telomere Shortening genetics, Hematopoiesis physiology, Telomere Shortening physiology
- Abstract
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance., (© 2021. The Author(s).)
- Published
- 2021
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27. Evolutionary action score identifies a subset of TP53 mutated myelodysplastic syndrome with favorable prognosis.
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Kanagal-Shamanna R, Montalban-Bravo G, Katsonis P, Sasaki K, Class CA, Jabbour E, Sallman D, Hunter AM, Benton C, Chien KS, Luthra R, Bueso-Ramos CE, Kadia T, Andreeff M, Komrokji RS, Al Ali NH, Short N, Daver N, Routbort MJ, Khoury JD, Patel K, Ganan-Gomez I, Wei Y, Borthakur G, Ravandi F, Do KA, Soltysiak KA, Lichtarge O, Medeiros LJ, Kantarjian H, and Garcia-Manero G
- Subjects
- Humans, Models, Molecular, Mutation, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes pathology, Prognosis, Myelodysplastic Syndromes genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2021
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28. Type I interferon upregulation and deregulation of genes involved in monopoiesis in chronic myelomonocytic leukemia.
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Montalban-Bravo G, Darbaniyan F, Kanagal-Shamanna R, Ganan-Gomez I, Class CA, Sasaki K, Naqvi K, Wei Y, Yang H, Soltysiak KA, Chien KS, Bueso-Ramos C, Do KA, Kantarjian H, and Garcia-Manero G
- Subjects
- Female, Humans, Male, Middle Aged, Gene Expression Regulation, Neoplastic drug effects, Interferon Type I administration & dosage, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic metabolism, Leukemia, Myelomonocytic, Chronic pathology, Myelopoiesis drug effects, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Up-Regulation drug effects
- Abstract
Chronic myelomonocytic leukemia (CMML) is characterized by myelomonocytic bias and monocytic proliferation. Whether cell-intrinsic innate immune or inflammatory upregulation mediate disease pathogenesis and phenotype or whether the degree of aberrant monocytic differentiation influences outcomes remains unclear. We compared the transcriptomic features of bone marrow CD34+ cells from 19 patients with CMML and compared to healthy individuals. A total of 1495 genes had significantly differential expression in CMML (q<0.05, fold change>2), including 1271 genes that were significantly upregulated and 224 that were significantly downregulated in CMML. Top upregulated genes were associated with interferon (IFN) alpha and beta signaling, chemokine receptors, IFN gamma, G protein-coupled receptor ligand signaling, and genes involved in immunomodulatory interactions between lymphoid and non-lymphoid cells. Additionally, 6 gene sets were differentially upregulated and 139 were significantly downregulated in patients with myeloproliferative compared to myelodysplastic CMML. A total of 23 genes involved in regulation of monopoiesis were upregulated in CMML compared to healthy controls. We developed a prediction model using Cox regression including 3 of these genes, which differentiated patients into two prognostic subsets with distinct survival outcomes. This data warrants further evaluation of the roles and therapeutic potential of type I IFN signaling and monopoiesis in CMML., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2021
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29. LILRB4 expression in chronic myelomonocytic leukemia and myelodysplastic syndrome based on response to hypomethylating agents.
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Chien KS, Class CA, Montalban-Bravo G, Wei Y, Sasaki K, Naqvi K, Ganan-Gomez I, Yang H, Soltysiak KA, Kanagal-Shamanna R, Do KA, Kantarjian HM, and Garcia-Manero G
- Subjects
- Humans, Immunotherapy, Membrane Glycoproteins, Receptors, Immunologic genetics, Up-Regulation, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Juvenile, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
LILRB4 is expressed in AML M4/M5 cells and negatively regulates immune cell activation via T-cell suppression. Its expression and role in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS) are unknown. We investigated LILRB4 expression in 19 CMML and 27 MDS patients and correlated it with response to subsequent hypomethylating agent (HMA) therapy. LILRB4 RNA expression was increased in CMML patients when compared to MDS patients and healthy controls ( q < 0.1) and slightly increased in patients who responded to HMAs ( q > 0.1). Pathway analysis revealed upregulation of PD-1 signaling, CTLA-4 signaling, and inflammatory response, and gene correlates were positively associated with CTLA-4 expression. Given current modest results with immunotherapy in myeloid malignancies, further investigation of LILRB4 as an immune checkpoint inhibitor target is needed. With the positive correlation between LILRB4 and CTLA-4 expression, combining anti-LILRB4 and anti-CTLA-4 agents may be a novel therapeutic approach in myeloid malignancies that warrants larger studies.
- Published
- 2020
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30. Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes.
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Montalban-Bravo G, Class CA, Ganan-Gomez I, Kanagal-Shamanna R, Sasaki K, Richard-Carpentier G, Naqvi K, Wei Y, Yang H, Soltysiak KA, Chien K, Bueso-Ramos C, Do KA, Kantarjian H, and Garcia-Manero G
- Subjects
- Aged, Antigens, CD34 metabolism, Bone Marrow metabolism, Disease Progression, Female, Humans, Inflammation, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic metabolism, Male, Middle Aged, Myelodysplastic Syndromes metabolism, Phenotype, Prognosis, Protein Kinases metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Myelodysplastic Syndromes diagnosis, Necroptosis, Transcriptome
- Abstract
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n = 46) or after (n = 18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-Seq. Compared with healthy controls, expression levels of MLKL (CMML: 2.09 log2FC, p = 0.0013; MDS: 1.89 log2FC, p = 0.003), but not RIPK1 or RIPK3, were significantly upregulated. Higher expression levels of MLKL were associated with lower hemoglobin levels at diagnosis (-0.19 log2FC per 1 g/dL increase of Hgb, p = 0.03). Significant reduction in MLKL levels was observed after HMA therapy (-1.06 log2FC, p = 0.05) particularly among nonresponders (-2.89 log2FC, p = 0.06). Higher RIPK1 expression was associated with shorter survival (HR 1.92, 95% CI 1.00-3.67, p = 0.049 by Cox proportional hazards). This data provides further support for a role of necroptosis in MDS, and potentially response to HMAs and prognosis. This data also indicate that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS.
- Published
- 2020
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31. NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy.
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Montalban-Bravo G, Kanagal-Shamanna R, Sasaki K, Patel K, Ganan-Gomez I, Jabbour E, Kadia T, Ravandi F, DiNardo C, Borthakur G, Takahashi K, Konopleva M, Komrokji RS, DeZern A, Kuzmanovic T, Maciejewski J, Pierce S, Colla S, Sekeres MA, Kantarjian H, Bueso-Ramos C, and Garcia-Manero G
- Subjects
- Adult, Aged, Aged, 80 and over, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Middle Aged, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Myelodysplastic-Myeloproliferative Diseases genetics, Myelodysplastic-Myeloproliferative Diseases mortality, Nucleophosmin, Remission Induction, Retrospective Studies, Survival Analysis, Treatment Outcome, Young Adult, Mutation, Myelodysplastic-Myeloproliferative Diseases diagnosis, Myelodysplastic-Myeloproliferative Diseases drug therapy, Nuclear Proteins genetics
- Abstract
Nucleophosmin ( NPM1 ) mutations are common in acute myeloid leukemia and are associated with high remission rates and prolonged survival with intensive chemotherapy. NPM1 mutations are rare in myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and the clinical outcomes of these patients, when treated with intensive chemotherapy, are unknown. We retrospectively evaluated the clinicopathologic characteristics and the impact of therapy in 31 patients with MDS or MDS/MPN and NPM1 mutations. Next-generation sequencing was performed at diagnosis in 22 patients. Median age was 62 years (range, 19-86). Twenty-four patients (77%) had normal karyotype, and all had multilineage dysplasia. Most patients could be classified as MDS with excess blasts (19/31, 61%). NPM1 mutations were detected at a median allele frequency of 0.38 (range, 0.09-0.49). Mutation burden did not correlate with bone marrow blast frequency, and its clearance seemed to be associated with decreased morphologic dysplasia. Ten of the 31 patients (32%) received cytotoxic chemotherapy, 20 (65%) hypomethylating agents, and 1 (4%) lenalidomide. Sequential sequencing was available in 16 (52%) patients, and mutation burden correlated with disease status and response to therapy. Patients treated with chemotherapy had higher complete response rates (90% vs 28%, P = .004), longer median progression-free survival (not reached vs 7.5 months, P = .023), and overall survival (not reached vs 16 months, P = .047). Intensive chemotherapy and allogeneic stem cell transplantation (SCT) may be associated with improved clinical outcomes in patients with NPM1 -mutated MDS or MDS/MPN who are candidates for this form of therapy., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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32. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice.
- Author
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Wei Y, Zheng H, Bao N, Jiang S, Bueso-Ramos CE, Khoury J, Class C, Lu Y, Lin K, Yang H, Ganan-Gomez I, Starczynowski DT, Do KA, Colla S, and Garcia-Manero G
- Subjects
- Animals, Bone Marrow metabolism, Bone Marrow pathology, Chromatin genetics, Chromatin metabolism, Flow Cytometry, Gene Expression Profiling, Hematopoietic Stem Cells metabolism, Histones metabolism, Humans, Immunomodulation, Jumonji Domain-Containing Histone Demethylases metabolism, Methylation, Mice, Mice, Knockout, Mice, Transgenic, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Phenotype, Gene Expression, Hematopoiesis genetics, Immunity, Innate genetics, Jumonji Domain-Containing Histone Demethylases genetics, Signal Transduction
- Abstract
KDM6B is an epigenetic regulator that mediates transcriptional activation during differentiation, including in bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Overexpression of KDM6B has been reported in BM HSPCs of patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Whether the overexpression of KDM6B contributes to the pathogenesis of these diseases remains to be elucidated. To study this, we generated a Vav-KDM6B mouse model, which overexpresses KDM6B in the hematopoietic compartment. KDM6B overexpression alone led to mild hematopoietic phenotype, and chronic innate immune stimulation of Vav-KDM6B mice with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS) resulted in significant hematopoietic defects. These defects recapitulated features of MDS and CMML, including leukopenia, dysplasia, and compromised repopulating function of BM HSPCs. Transcriptome studies indicated that KDM6B overexpression alone could lead to activation of disease-relevant genes such as S100a9 in BM HSPCs, and when combined with innate immune stimulation, KDM6B overexpression resulted in more profound overexpression of innate immune and disease-relevant genes, indicating that KDM6B was involved in the activation of innate immune signaling in BM HSPCs. Finally, pharmacologic inhibition of KDM6B with the small molecule inhibitor GSK-J4 ameliorated the ineffective hematopoiesis observed in Vav-KDM6B mice. This effect was also observed when GSK-J4 was applied to the primary BM HSPCs of patients with MDS by improving their repopulating function. These results indicate that overexpression of KDM6B mediates activation of innate immune signals and has a role in MDS and CMML pathogenesis, and that KDM6B targeting has therapeutic potential in these myeloid disorders., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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33. ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma.
- Author
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Marchesini M, Ogoti Y, Fiorini E, Aktas Samur A, Nezi L, D'Anca M, Storti P, Samur MK, Ganan-Gomez I, Fulciniti MT, Mistry N, Jiang S, Bao N, Marchica V, Neri A, Bueso-Ramos C, Wu CJ, Zhang L, Liang H, Peng X, Giuliani N, Draetta G, Clise-Dwyer K, Kantarjian H, Munshi N, Orlowski R, Garcia-Manero G, DePinho RA, and Colla S
- Subjects
- DNA Damage, DNA Repair, Homologous Recombination, Humans, Nuclear Factor 45 Protein genetics, Nuclear Factor 45 Protein metabolism, Splicing Factor U2AF metabolism, Tumor Cells, Cultured, Y-Box-Binding Protein 1 metabolism, Multiple Myeloma genetics, Nuclear Factor 45 Protein physiology, RNA Splicing genetics
- Abstract
Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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34. PDE4 Differential Expression Is a Potential Prognostic Factor and Therapeutic Target in Patients With Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia.
- Author
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Chamseddine AN, Cabrero M, Wei Y, Ganan-Gomez I, Colla S, Takahashi K, Yang H, Bohannan ZS, and Garcia-Manero G
- Subjects
- Adult, Aged, Aged, 80 and over, Bone Marrow pathology, Combined Modality Therapy, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Interleukin-8 genetics, Interleukin-8 metabolism, Kaplan-Meier Estimate, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic mortality, Male, Middle Aged, Molecular Targeted Therapy, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes mortality, Phosphodiesterase 4 Inhibitors therapeutic use, Prognosis, Protein Isoforms, Retreatment, Severity of Illness Index, Treatment Outcome, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Gene Expression, Leukemia, Myelomonocytic, Chronic genetics, Myelodysplastic Syndromes genetics
- Abstract
Background (or Purpose): Inflammation has an essential role in the pathogenesis of myelodysplastic syndromes (MDS). Its expression is controlled by phosphodiesterase 4 (PDE4). Thus, PDE4 inhibitors might be useful therapeutic targets for MDS., Patients (or Materials) and Methods: We evaluated the expression of each isoform of PDE4 (A, B, C, and D) using transcriptomic profiling and examined the potential impact on the outcome of patients with MDS in terms of survival and response to hypomethylating agents. Total RNA was extracted from CD34(+) bone marrow hematopoietic cells from healthy individuals (n = 10) and patients with MDS (n = 24) or chronic myelomonocytic leukemia (n = 19)., Results: The study cohort had a median follow-up period of 21.2 months (range, 0.2-68 months) and a median overall survival of 17.6 months (95% confidence interval, 9.6-25.6). The main finding of the present study was that PDE4 mean expression was generally higher in patients with MDS than in healthy individuals. Also, upregulated PDE4 expression seemed to have a possible negative effect on survival (P > .05). Moreover, lower, compared with higher, mean PDE4A and PDE4C expression is indicative of a response to a hypomethylating agent (0.09 and 0.03 vs. 0.54 and 0.49, respectively; P > .05)., Conclusion: These results should be confirmed in a larger patient cohort. PDE4 expression could be an effective potential prognostic factor and therapeutic target for patients with MDS and chronic myelomonocytic leukemia. The role of PDE4 inhibitors should be explored in vitro against MDS cell lines and in preclinical mouse models of MDS., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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35. Down-regulation of EZH2 expression in myelodysplastic syndromes.
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Cabrero M, Wei Y, Yang H, Ganan-Gomez I, Bohannan Z, Colla S, Marchesini M, Bravo GM, Takahashi K, Bueso-Ramos C, and Garcia-Manero G
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Down-Regulation, Enhancer of Zeste Homolog 2 Protein, Female, Follow-Up Studies, Humans, Male, Middle Aged, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Neoplasm Staging, Prognosis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tumor Cells, Cultured, Biomarkers, Tumor genetics, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Jumonji Domain-Containing Histone Demethylases genetics, Myelodysplastic Syndromes genetics, Polycomb Repressive Complex 2 genetics
- Abstract
EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
36. Downregulation of Protection of Telomeres 1 expression in myelodysplastic syndromes with 7q deletion.
- Author
-
Cabrero M, Yu Y, Verma A, Yang H, Colla S, Jia Y, Zheng H, Bohannan Z, Ganan-Gomez I, Futreal A, Takahashi K, Chin L, Kantarjian H, Pellagatti A, Bowman T, Boultwood J, Garcia-Manero G, and Wei Y
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes mortality, Shelterin Complex, Telomere-Binding Proteins genetics, Chromosome Deletion, Chromosomes, Human, Pair 7 genetics, Down-Regulation, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes metabolism, Telomere-Binding Proteins biosynthesis
- Published
- 2016
- Full Text
- View/download PDF
37. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.
- Author
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Colla S, Ong DS, Ogoti Y, Marchesini M, Mistry NA, Clise-Dwyer K, Ang SA, Storti P, Viale A, Giuliani N, Ruisaard K, Ganan Gomez I, Bristow CA, Estecio M, Weksberg DC, Ho YW, Hu B, Genovese G, Pettazzoni P, Multani AS, Jiang S, Hua S, Ryan MC, Carugo A, Nezi L, Wei Y, Yang H, D'Anca M, Zhang L, Gaddis S, Gong T, Horner JW, Heffernan TP, Jones P, Cooper LJ, Liang H, Kantarjian H, Wang YA, Chin L, Bueso-Ramos C, Garcia-Manero G, and DePinho RA
- Subjects
- Animals, Haploinsufficiency, Humans, Mice, Myelodysplastic Syndromes pathology, Nuclear Proteins genetics, RNA Splicing, Ribonucleoproteins genetics, Serine-Arginine Splicing Factors, Cell Differentiation genetics, Hematopoiesis genetics, Myelodysplastic Syndromes genetics, Telomere
- Abstract
Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
38. [Changes in mitochondrial function induced by dequalinium precede oxidative stress and apoptosis in the human prostate cancer cell line PC-3].
- Author
-
Makowska K, Estan MC, Ganan-Gomez I, Boyano-Adanez MC, Garcia-Perez AI, and Sancho P
- Subjects
- Apoptosis, Caspase 3 metabolism, Cell Line, Tumor, Cell Survival, Dose-Response Relationship, Drug, Humans, Male, Mitochondria drug effects, Reactive Oxygen Species metabolism, Antineoplastic Agents pharmacology, Dequalinium pharmacology, Membrane Potential, Mitochondrial, Mitochondria metabolism, Oxidative Stress, Prostatic Neoplasms metabolism
- Abstract
Mitochondria play central roles in diverse physiological and pathological conditions associated with cell survival and death. Delocalized lipophilic cations, such as dequalinium (DQA), are accumulated in cancer cells attracted by the highly negative mitochondrial transmembrane potential of these cells. DQA showed a potent anticancer activity in cells from different malignancies. Here, we report the effect of DQA on PC-3 prostate cancer cells. Incubation with DQA at concentrations between 1.5 and 100 microM from 24 to 48 h decreases cell viability. The decrease in cell viability together with a loss of mitochondrial transmembrane potential induced an increase in reactive oxygen species production and cell death via caspase-3 dependent apoptotic pathway. QA was shown to cause moderate to strong cell death in a time and concentration dependent manner, causing a most advantageous effect at a concentration of 10 microM applied for a long 48 h time period, which might be a consequence of the kinetics of intracellular DQA accumulation in mitochondria, but also of the mechanisms of DQA-induced cell death. This data shows DQA as a promising agent against the human prostate cancer PC-3 cell line, activating the caspase-3 dependent apoptotic pathway. This fact might be beneficial for possible future applications in cancer therapy.
- Published
- 2014
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