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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive proliferation of myeloid cells. The COVID-19 pandemic has raised concerns regarding the impact of SARS-CoV-2 on patients with malignancies, particularly those with CML. This study aimed to investigate the effects of SARS-CoV-2 proteins on CML cell viability and the protective role of vitamin K2 (VK2) in conjunction with imatinib. Experiments conducted on K562 CML cells demonstrated that the SARS-CoV-2 envelope protein induces cytotoxicity and activates caspase 3/7, which are key markers of apoptosis. VK2 mitigated these cytotoxic effects and decreased cytokine production while inhibiting colony formation. Furthermore, the combination of VK2 with imatinib significantly reduced cellular proliferation, diminished mitochondrial membrane potential, and markedly suppressed colony formation. These findings suggest that VK2 protects CML cells from SARS-CoV-2-induced cytotoxicity and enhances the therapeutic efficacy of imatinib, presenting a potential strategy to improve CML treatment during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment outcomes in chronic myeloid leukemia (CML) have improved in recent years because of the use of tyrosine kinase inhibitors. However, treatment responses to myeloid blast-phase CML (MBP-CML) are still unsatisfactory. In this paper, we summarize the biological mechanisms of progression to MBP and the most frequently used treatment regimens for MBP-CML. We also review why some patients develop resistance to tyrosine kinase inhibitors. Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered. [ABSTRACT FROM AUTHOR]

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin's aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML. [ABSTRACT FROM AUTHOR]

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection. [ABSTRACT FROM AUTHOR]

Platelets are essential blood components that maintain hemostasis, prevent excessive bleeding, and facilitate wound healing. Reduced platelet counts are implicated in various diseases, including leukemia, hepatitis, cancer, and Alzheimer's disease. Enhancing megakaryocytic differentiation is a promising strategy to increase platelet production. Compound K (CK), a major bioactive metabolite of ginsenosides from Panax ginseng, has demonstrated anti-cancer and neuroprotective properties. In this study, we investigated the effects of CK on megakaryocytic differentiation and apoptosis in chronic myeloid leukemia (CML) cell lines K562 and Meg-01. CK treatment significantly upregulated the mRNA expression of key megakaryocytic differentiation markers, including CD61, CD41, and CD42a, and promoted the formation of large, multinucleated cells in K562 cells. Additionally, flow cytometry analysis revealed that CK at 5 µM induced apoptosis, a critical process in thrombocytopoiesis, in both K562 and Meg-01 cells. RT2 Profiler PCR array analysis further identified a marked increase in the expression of genes associated with the activation of the NLRP3 inflammasome in CK-treated K562 and Meg-01 cells. This study is the first to demonstrate that CK promotes megakaryocytic differentiation and apoptosis through the activation of the ERK/EGR1 and NLRP3 inflammasome pathways. These findings suggest that CK may enhance platelet production, indicating its potential as a therapeutic candidate for platelet-related disorders and other associated diseases. [ABSTRACT FROM AUTHOR]

Histone H1 is involved in the regulation of chromatin structure. Human somatic cells express up to seven subtypes. The variability in the proportions of somatic H1s (H1 complement) is one piece of evidence supporting their functional specificity. Alterations in the protein levels of different H1 subtypes have been observed in cancer, suggesting their potential as biomarkers and that they might play a role in disease development. We have developed a mass spectrometry-based (MS) parallel reaction monitoring (PRM) assay suitable for the quantification of H1 subtypes. Our PRM method is based on the quantification of unique peptides for each subtype, providing high specificity. Evaluation of the PRM performance on three human cell lines, HeLa, K562, and T47D, showed high reproducibility and sensitivity. Quantification values agreed with the electrophoretic and Western blot data, indicating the accuracy of the method. We used PRM to quantify the H1 complement in peripheral blood samples of healthy individuals and chronic myeloid leukemia (CML) patients. In CML, the first line of therapy is a tyrosine kinase inhibitor, imatinib. Our preliminary data revealed differences in the H1 complement in CML patients between imatinib responders and non-responders. These results support further research to determine if the H1 content or subtype composition could help predict imatinib response. [ABSTRACT FROM AUTHOR]

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). [ABSTRACT FROM AUTHOR]

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment. [ABSTRACT FROM AUTHOR]

The advent of tyrosine kinase inhibitors (TKIs) has changed the natural history of chronic myeloid leukemia (CML), and the transformation from the chronic phase to the blast phase (BP) is currently an uncommon situation. However, it is one of the major remaining challenges in the management of this disease, as it is associated with dismal outcomes. We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, she suffered an early relapse after allo-HSCT with the acquisition of the T315I mutation in ABL1. Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes. [ABSTRACT FROM AUTHOR]

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN. [ABSTRACT FROM AUTHOR]

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients' coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by bone marrow expansion and the proliferation of one or more myeloid cell lineages, predominantly driven by the expression of the constitutively active fusion product tyrosine kinase BCR:ABL1. Rarely, CML patients directly develop a blast crisis (BC), mostly of myeloid origin. CML at blast crisis with a T-cell phenotype at diagnosis, without any prior history of CML, is extremely rare. Herein, we describe one rare CML case, in a young man showing an unusual and early T-lymphoid blastic crisis at diagnosis, as the first onset of a previously unknown CML. The multidisciplinary collaboration between laboratorians and clinicians for the diagnosis and management of this atypical case was crucial in outlining both a targeted pharmacological treatment and a successful hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions. [ABSTRACT FROM AUTHOR]

The Lucena 1 cell line, derived from the human chronic myeloid leukemia cell line K562 under selective pressure of vincristine supplementation, exhibits multidrug resistance (MDR). This study aims to explore and elucidate the underlying mechanisms driving MDR in the Lucena 1 cell line. A proteomic analysis comparing K562 and Lucena 1 revealed qualitative differences, with a focus on the ATP-dependent efflux pump, Translocase ABCB1, a key contributor to drug resistance. Tubulin analysis identified two unique isoforms, Tubulin beta 8B and alpha chain-like 3, exclusive to Lucena 1, potentially influencing resistance mechanisms. Additionally, the association of Rap1A and Krit1 in cytoskeletal regulation and the presence of STAT1, linked to the urea cycle and tumor development, offered insights into Lucena 1's distinctive biology. The increased expression of carbonic anhydrase I suggested a role in pH regulation. The discovery of COP9, a tumor suppressor targeting p53, further highlighted the Lucena 1 complex molecular landscape. This study offers new insights into the MDR phenotype and its multifactorial consequences in cellular pathways. Thus, unraveling the mechanisms of MDR holds promise for innovating cancer models and antitumor targeted strategies, since inhibiting the P-glycoprotein (P-gp)/ABCB1 protein is not always an effective approach given the associated treatment toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The pathophysiology of leukemia has been studied in the most detailed manner among all human cancers. In this review, acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) with RUNX1-RUNX1T1 were selected to consider minimal requirements for cancer initiation based on a simplified model. Even if its completed form is complex, cancer originates from one or two events that happened to a single cell. A simplified model can play a role in understanding how cancer initiates at the beginning. The pathophysiology of leukemia has been studied in the most detailed manner among all human cancers. In this review, based on milestone papers and the latest research developments in hematology, acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) with RUNX1-RUNX1T1 are selected to consider minimal requirements for cancer initiation. A one-hit model can be applied to the initiation of APL and CML whereas a two-hit model is more suitable to the initiation of AML with RUNX1-RUNX1T1 and other AMLs. Even in cancer cells with multiple genetic abnormalities, there must be a few mutant genes critical for the mutant clone to survive and proliferate. Such genes should be identified and characterized in each case in order to develop individualized target therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: We aimed to evaluate the extent to which clinical trials represent countries with different socio-demographic indexes and the availability of tyrosine kinase inhibitors for chronic myeloid leukemia. We found a significant lack of availability for tyrosine kinase inhibitors on the global level, and a lack of equitable distribution of trials across countries is an issue that needs to be addressed. Background: Evaluating clinical trial representation for countries with different socio-demographic index (SDI) and tyrosine kinase inhibitor (TKI) availability for chronic myeloid leukemia (CML). Methods: CML incidence rates (IRs) and disability-adjusted life years (DALYs) (1999–2019) from the Institute of Health Metrics and Evaluation were analyzed. Trials investigating TKI use in CML were obtained from ClinicalTrials.gov. Site data for eligible trials (N = 30) and DALYs were analyzed. TKI approvals, DALYs, and IRs were summarized by SDI. Results: North America (NA) had significant decreases in annual percent change (APC) in DALYs and incidence rates from 1999 to 2004. IRs were highest in Europe and Central Asia (ECA) and NA, while DALYs were highest in South Asia (SAsia) and Sub-Saharan Africa (SSA). Countries in the high-SDI quintile were likely to have lower DALYs than lower-SDI quintiles. Differences in regional DALYs vs. sites in TKI trials were significant for SAsia, SSA, and ECA. High-SDI countries were included in all 30 trials, and TKI approvals were prominent in high-SDI (142) vs. low-SDI (14) countries. Conclusions: The inclusion of disproportionately affected countries during the design of and recruitment into clinical trials should occur, as should TKI availability. The lack of representation demonstrates healthcare disparities. [ABSTRACT FROM AUTHOR]

Simple Summary: Tyrosine kinase inhibitors (TKIs), particularly imatinib, have afforded Chronic Myeloid Leukemia (CML) patients long-term remission. This revolution in leukemia treatment is unfortunately accompanied by the fact that treatment interruption, in most cases, leads to the re-emergence of BCR-ABL-leukemia cells, caused by leukemia stem cells, that are insensitive to TKI treatment. Moreover, TKIs paradoxically induce a quiescent state in leukemia stem and progenitor cells. Current CML studies focus on these quiescent leukemia stem cells in order to reactivate them and restore TKI sensitivity. We show here that under TKI treatment, leukemia stem cells retrieve motility in a reconstituted niche when incubated with SKF96365, a calcium channel inhibitor, and that this effect is dependent on RhoA activation by BCR-ABL independently of its tyrosine kinase activity. Altogether, these results suggest that SKF-96365 or its derived molecules could be interesting compounds for targeting quiescent CML stem and progenitor cells under TKI treatment. Background: A major issue in Chronic Myeloid Leukemia (CML) is the persistence of quiescent leukemia stem cells (LSCs) in the hematopoietic niche under tyrosine kinase inhibitor (TKI) treatment. Results: Here, using CFSE sorting, we show that low-proliferating CD34+ cells from CML patients in 3D co-culture hide under HS27A stromal cells during TKI treatment—a behavior less observed in untreated cells. Under the same conditions, Ba/F3p210 cells lose their spontaneous motility. In CML CD34+ and Ba/F3p210 cells, while Rac1 is completely inhibited by TKI, RhoA remains activated but is unable to signal to ROCK. Co-incubation of Ba/F3p210 cells with TKI, SKF-96365 (a calcium channel inhibitor), and EGF restores myosin II activation and amoeboid motility to levels comparable to untreated cells, sustaining the activation of ROCK. In CFSE+ CD34+ cells containing quiescent leukemic stem cells, co-incubation of TKI with SKF-96365 induced the expulsion of these cells from the HS27A niche. Conclusions: This study underscores the role of RhoA in LSC behavior under TKI treatment and suggests that SKF-96365 could remobilize quiescent CML LSCs through reactivation of the RhoA/ROCK pathway. [ABSTRACT FROM AUTHOR]

To investigate the impact of extrusion parameters on the formation of Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and acrylamide in plant-based meat analogues (PBMAs), the content changes and the correlations of compounds related to their formation were studied. The extrusion promoted CML, CEL and acrylamide formation, with more CEL being formed than CML. Variations in the moisture level and barrel temperature exerted a greater influence on the CML, CEL, acrylamide and α-dicarbonyl compounds than the screw speed and the feed rate. An increase in the moisture content led to a decrease in the CEL content, whereas it enhanced CML formation. The impact of moisture on acrylamide formation varied depending on whether low- or high-moisture extrusion was applied. Elevated temperatures promoted the accumulation of CEL, methylglyoxal and 2,3-butanedione while diminishing the accumulation of CML, acrylamide, glyoxal and 3-deoxyglucosone. CML and CEL were positively correlated with glyoxal and methylglyoxal, respectively. CEL and methylglyoxal were negatively correlated with protein and water content, whereas CML, glyoxal and 3-deoxyglucosone displayed positive correlations. In summary, higher moisture levels and feed rates and lower screw speeds and barrel temperatures are advantageous for producing PBMAs with lower CEL and total advanced glycation end-products contents, while lower or higher moisture contents, a lower feed rate and a higher barrel temperature are beneficial to reducing the acrylamide content. [ABSTRACT FROM AUTHOR]

Soil salinity is a major abiotic stress limiting crop production globally. Oat (Avena sativa) is an annual cereal with a strong salt tolerance, a high yield, and nutritional quality, although the mechanisms underlying its salt stress response remain largely unknown. We examined the physiological and transcriptomic responses of A. sativa seedlings to salt stress in tolerant cultivar Qingyongjiu 195 and sensitive cultivar 709. Under salt stress, Qingyongjiu 195 maintained a higher photosynthetic efficiency, antioxidant enzymes activity, and leaf K+ accumulation but a lower Na+ uptake than 709. RNA-seq revealed 6616 differentially expressed genes (DEGs), including 4265 up- and 2351 downregulated. These were enriched in pathways like plant–pathogen interaction, phenylpropanoid biosynthesis, and MAPK signaling. We specifically highlight DEGs involved in photosynthesis (chlG, CP47 psbB, COX2, LHCB) and antioxidants (trxA, GroES). Qingyongjiu 195 also appeared to enhance K+ uptake via KAT1 and AKT2 and sequester Na+ in vacuoles via NHX2. Additionally, HKT restricted Na+ while promoting K+ transport to shoots, maintaining K+/Na+. The expression levels of CAX, ACA, CML, CaM, and CDPK in Qingyongjiu 195 were higher than those in 709. Oats regulated Ca2+ concentration through CAX and ACA after salt stress, decoded Ca2+ signals through CML, and then transferred Ca2+ signals to downstream receptors through the Ca2+ sensors CaM and CDPK, thereby activating K+/Na+ transporters, such as SOS1 and NHX, etc. Our results shed light on plant salt stress response mechanisms and provide transcriptomic resources for molecular breeding in improving salt tolerance in oats. [ABSTRACT FROM AUTHOR]

Background: ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. Patients and Methods: The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. Results: 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/μL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078–0.711); p = 0.010]. Conclusions: The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation. [ABSTRACT FROM AUTHOR]

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine multicentric lymphoma is a common hematopoietic neoplasm in dogs that initially responds well to treatment but often relapses due to chemotherapy resistance. Evaluating treatment response is crucial. Ultrasound can differentiate between benign and malignant lymph nodes, but its use post chemotherapy is limited. This study compared ultrasound parameters of lymphomatous lymph nodes during the first three weeks post treatment with normal lymph nodes from healthy dogs. Ultrasound, including B-mode and elastography, was performed pre-treatment and weekly for three weeks post treatment. Lymphomatous lymph nodes were categorized into partial response and stable disease groups. Ultrasound scores, combining B-mode and elastography parameters, were significantly higher in lymphomatous lymph nodes than normal lymph nodes. Lymphomatous lymph nodes at pre-treatment had higher values than post-treatment. Ultrasound scores significantly differed among healthy, partial response, and stable disease groups. Therefore, ultrasound can be effectively used in conjunction with the conventional method to evaluate treatment response. Canine multicentric lymphoma (CML) is a prevalent hematopoietic neoplasm that initially responds well to treatment but often relapses due to chemotherapy resistance. Evaluation of treatment response is essential for effective management. Ultrasound (US) can differentiate between benign and lymphomatous lymph nodes (LLNs). However, its utility in monitoring LLNs post chemotherapy is limited. This study aimed to compare US parameters of LLNs during the first 3 weeks post treatment and evaluate their diagnostic performance compared with the conventional method for assessing treatment response. This study included 95 LLNs from 15 dogs with CML and 60 normal lymph nodes (NLNs) from 15 healthy dogs. US, including B-mode and elastography, was performed pre-treatment and weekly for 3 weeks post treatment, and compared with the results of NLNs. LLNs were categorized into partial response and stable disease groups using the conventional method. US scores were established by combining B-mode and elastography parameters. The results showed significantly higher values of LLNs in the short-to-long axis ratio, elastographic scales, and blue-to-green color histogram compared with NLNs. Additionally, LLNs at pre-treatment had significantly higher values than LLNs post treatment. US scores significantly differed among the healthy, partial response, and stable disease groups. In conclusion, B-mode US, elastography, and US scores demonstrated changes during chemotherapy consistent with the conventional method and can be used in conjunction with the conventional method to evaluate the treatment response of CML. [ABSTRACT FROM AUTHOR]

While BCR::ABL1 tyrosine kinase inhibitors have transformed the treatment paradigm for chronic myeloid leukemia (CML), disease progression and treatment resistance due to BCR::ABL1-dependent and BCR::ABL1-independent mechanisms remain a therapeutic challenge. Natural compounds derived from plants have significantly contributed to cancer pharmacotherapy. This study investigated the efficacy of an active component of Leea indica, a local medicinal plant, in CML. Using high-performance liquid chromatography–electrospray ionization–mass spectrometry, a chemical constituent from L. indica extract was isolated and identified as gallic acid. Commercially obtained gallic acid was used as a chemical standard. Gallic acid from L. indica inhibited proliferation and induced apoptosis in CML cell lines, as did the chemical standard. Furthermore, gallic acid induced apoptosis and decreased the colony formation of primary CML CD34+ cells. The combination of isolated gallic acid or its chemical standard with BCR::ABL1 tyrosine kinase inhibitors resulted in a significantly greater inhibition of colony formation and cell growth compared to a single drug alone. Mechanistically, CML cells treated with gallic acid exhibited the disruption of multiple oncogenic pathways including ERK/MAPK, FLT3 and JAK/STAT, as well as impaired mitochondrial respiration. Rescue studies showed that gallic acid is significantly less effective in inducing apoptosis in mitochondrial respiration-deficient ρ0 cells compared to wildtype cells, suggesting that the action of gallic acid is largely through the inhibition of mitochondrial respiration. Our findings highlight the therapeutic potential of L. indica in CML and suggest that gallic acid may be a promising lead chemical constituent for further development for CML treatment. [ABSTRACT FROM AUTHOR]

This mathematical model delves into the dynamics of the immune system during Chronic Myeloid Leukemia (CML) therapy with imatinib. The focus lies in elucidating the allergic reactions induced by imatinib, specifically its impact on T helper (Th) cells and Treg cells. The model integrates cellular interactions, drug pharmacokinetics, and immune responses to unveil the mechanisms underlying the dominance of Th2 over Th1 and Treg cells, leading to allergic manifestations. Through a system of coupled delay differential equations, the interplay between healthy and leukemic cells, the influence of imatinib on T cell dynamics, and the emergence of allergic reactions during CML therapy are explored. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. Methods: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. Results: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. Conclusions: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies. [ABSTRACT FROM AUTHOR]

Geriatric assessment management is a multidimensional tool used to evaluate prognosis for clinical outcomes and targets for interventions in older adults with cancer receiving chemotherapy. In this review, we evaluated the possible application of geriatric assessment management (GAM) in hematological malignancies. In older patients with Diffuse Large B Cell Lymphoma, GAM might be helpful in both predicting planned hospital admissions and improving quality of life. In chronic myeloid leukemia, the Charlson Comorbidity Index demonstrates how comorbidities could affect treatment compliance and overall outcomes. In multiple myeloma, the application of different scores such as the International Myeloma Working Group Frailty Index and the Revised Myeloma Comorbidity Index can identify frail patients who need suitable interventions in treatment plan (reducing drug dose or changing treatment). Therefore, including GAM in the management plan of older patients with hematological malignancies may direct and optimize cancer care. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease lies in the formation of a chimeric oncogene BCR–ABL1. The protein product of this gene, p210 BCR–ABL1, exhibits abnormally high constitutive tyrosine kinase activity. Over recent decades, several targeted tyrosine kinase inhibitors (TKIs) directed against BCR–ABL1 have been developed and introduced into clinical practice. These inhibitors suppress BCR–ABL1 activity through various mechanisms. Furthermore, the advent of RNA interference technology has enabled the highly specific inhibition of BCR–ABL1 transcript expression using small interfering RNA (siRNA). This experimental evidence opens avenues for the development of a novel therapeutic strategy for CML, termed siRNA therapy. The review delves into molecular genetic mechanisms underlying the pathogenesis of CML, challenges in CML therapy, potential molecular targets for drug development, and the latest results from the application of siRNAs in in vitro and in vivo CML models. [ABSTRACT FROM AUTHOR]

Background: In genomics, highly sensitive point mutation detection is particularly relevant for cancer diagnosis and early relapse detection. Next-generation sequencing combined with unique molecular identifiers (UMIs) is known to improve the mutation detection sensitivity. Methods: We present an open-source bioinformatics framework named Interface for Point Mutation Identification (IMPI) with a graphical user interface (GUI) for processing especially small-scale NGS data to identify variants. IMPI ensures detailed UMI analysis and clustering, as well as initial raw read processing, and consensus sequence building. Furthermore, the effects of custom algorithm and parameter settings for NGS data pre-processing and UMI collapsing (e.g., UMI clustered versus unclustered (raw) reads) can be investigated. Additionally, IMPI implements optimization and quality control methods; an evolution strategy is used for parameter optimization. Results: IMPI was designed, implemented, and tested using BCR::ABL1 fusion gene kinase domain sequencing data. In summary, IMPI enables a detailed analysis of the impact of UMI clustering and parameter setting changes on the measured allele frequencies. Conclusions: Regarding the BCR::ABL1 data, IMPI's results underlined the need for caution while designing specialized single amplicon NGS approaches due to methodical limitations (e.g., high PCR-mediated recombination rate). This cannot be corrected using UMIs. [ABSTRACT FROM AUTHOR]

The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the usefulness of an attachable video laryngoscope (AVL) by attaching a camera and a monitor to a conventional Macintosh laryngoscope (CML). Normal and tongue edema airway scenarios were simulated using a manikin. Twenty physicians performed tracheal intubations using CML, AVL, Pentax Airwayscope® (AWS), and McGrath MAC® (MAC) in each scenario. Ten physicians who had clinical experience in using tracheal intubation were designated as the skilled group, and another ten physicians who were affiliated with other departments and had little clinical experience using tracheal intubation were designated as the unskilled group. The time required for intubation and the success rate were recorded. The degree of difficulty of use and glottic view assessment were scored by participants. All 20 participants successfully completed the study. There was no difference in tracheal intubation success rate and intubation time in the normal airway scenario in both skilled and unskilled groups. In the experienced group, AWS had the highest success rate (100%) in the tongue edema airway scenario, followed by AVL (60%), MAC (60%), and CML (10%) (p = 0.001). The time required to intubate using AWS was significantly shorter than that with AVL (10.2 s vs. 19.2 s) or MAC (10.2 s vs. 20.4 s, p = 0.007). The difficulty of using AVL was significantly lower than that of CML (7.8 vs. 2.8; p < 0.001). For the experienced group, AVL was interpreted as being inferior to AWS but better than MAC. Similarly, in the unskilled group, AVL had a similar success rate and tracheal intubation time as MAC in the tongue edema scenario, but this was not statistically significant. The difficulty of using AVL was significantly lower than that of CML (8.8 vs. 3.3; p < 0.001). AVL may be an alternative for VL. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a noticeable dearth of information regarding chronic myeloid leukemia (CML) within the Gulf region. This study seeks to address this gap by offering comprehensive insights into the status of CML in the Gulf, encompassing aspects such as diagnosis, testing, treatment objectives, toxicities, and discontinuation. Through a survey completed by 15 experts and subsequent discussions, this research sheds light on the management and treatment approaches for CML within the region. Remarkably, the practices observed among these experts closely align with global standards, although unique challenges pertinent to the Gulf region were distinctly identified during the discourse. Studies on chronic myeloid leukemia (CML) in the Gulf region are scarce, consisting of a survey and expert meeting that included 15 experts in 2023 which discussed CML diagnosis, testing, treatment objectives, toxicities, and discontinuation in the Gulf region. Most patients were reported to be in first-line therapy, and the most common treatments were imatinib/imatinib generic in first-line and dasatinib in second- and third-lines. Mutation analysis was not reported to be routinely performed at the time of diagnosis but rather in case of progression to accelerated/blast phase or any sign of loss of response. While all participants were aware that BCR-ABL should be monitored every three months during the first year of treatment, 10% reported monitoring BCR-ABL every six months in practice due to test cost and lab capability. The most important first-line therapy objective was "achievement of major molecular response" (MMR) in younger patients and "overall survival" in older ones. The most important treatment objectives were "MMR" and "early molecular response followed by prolongation of overall survival" in the short term and "treatment-free remission" in the long term. The current practices in CML in the Gulf region appear to be similar to global figures. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitor (TKI) drugs have significantly improved chronic myeloid leukemia (CML) outcomes. Neopeptides from CML cells may induce specific immune responses, which are crucial for deep molecular (DMR) and treatment-free remission (TFR). In this study of Ethiopian patients with CML (n = 162), the HLA alleles and single-nucleotide polymorphisms of five cytokines revealed significant associations with clinical outcomes. Clinically unfavorable outcomes correlated with HLA alleles A*03:01/02, A*23:17:01, B*57:01/02/03, and HLA-DRB4*01:01 (p-value = 0.0347, p-value = 0.0285, p-value = 0.037, and p-value = 0.0127, respectively), while HLA-DRB4*01:03:01 was associated with favorable outcomes (p-value = 0.0058). After assigning values for the 'low', 'intermediate', and 'high' gene expression of the SNPs' respective cytokine genes, Kaplan–Meier estimates for relapse-free survival, adjusted for age, treatment duration, and relapse risk among patients after the administration of TKIs, indicated that a gene expression ratio above the overall median of TNF-α, IL-6, and the combination of TGF-β1/IL-10, IFNγ, and IL-6/IL-10 TGF-β1 was correlated with a higher likelihood of treatment failure ((RR: 3.01; 95% CI: 1.1–8.3; p-value = 0.0261) and (RR: 2.4; 95% CI: 1.1–5.2; p-value = 0.022), respectively). Multi-SNPs, surpassing single-SNPs, and HLA allele polymorphisms showed promise in predicting outcomes of patients with CML during TKI treatment, prompting further exploration into their potential utility. [ABSTRACT FROM AUTHOR]

Background: Recent research has identified alternative transcript variants of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) and insulin receptors (INSRs) as potential biomarkers for various types of cancer. The objective of this study was to assess the expression of LMNA/C and INSR transcript variants in peripheral blood mononuclear cells (PBMCs) of leukemia patients to investigate their potential as diagnostic biomarkers. Methods: Quantitative TaqMan reverse transcriptase polymerase chain reaction (RT-qPCR) was utilized to quantify the mRNA levels of LMNA/C (LMNA, LMNC, LMNAΔ10, and LMNAΔ50) as well as INSR (IR-A and IR-B) variants in PBMCs obtained from healthy individuals (n = 32) and patients diagnosed with primary leukemias (acute myeloid leukemia (AML): n = 17; acute lymphoblastic leukemia (ALL): n = 8; chronic myeloid leukemia (CML): n = 5; and chronic lymphocytic leukemia (CLL): n = 15). Results: Only LMNA and LMNC transcripts were notably present in PBMCs. Both exhibited significantly decreased expression levels in leukemia patients compared to the healthy control group. Particularly, the LMNC:LMNA ratio was notably higher in AML patients. Interestingly, IR-B expression was not detectable in any of the PBMC samples, precluding the calculation of the IR-A:IR-B ratio as a diagnostic marker. Despite reduced expression across all types of leukemia, IR-A levels remained detectable, indicating its potential involvement in disease progression. Conclusions: This study highlights the distinct expression patterns of LMNA/C and INSR transcript variants in PBMCs of leukemia patients. The LMNC:LMNA ratio shows promise as a potential diagnostic indicator for AML, while further research is necessary to understand the role of IR-A in leukemia pathogenesis and its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

With the discovery of tyrosine kinase inhibitors (TKIs), overall survival in patients with chronic myeloid leukemia (CML) now approaches that of the general population. While these TKIs have proven to be lifesaving, remaining on them lifelong creates both physical and financial burdens for patients. Recently, multiple trials have begun looking into the efficacy of trialing patients off these TKIs to see if they can sustain treatment-free remission (TFR). TFR eligibility is currently limited to a small population of patients with both robust and sustained responses to TKIs. Currently, for those who attempt a trial of TFR, the average success rates are promising, with anywhere from 38 to 54% of patients experiencing sustained TFR. For those who fail to maintain sustained TFR, safety results to date are reassuring, with almost all patients successfully responding to the re-initiation of TKIs, with death and disease progression being very rare complications. Moving forward, research is being conducted to more accurately risk stratify patients at diagnosis and pair them with optimized upfront treatment regimens aimed at increasing candidacy for the trial of TFR. [ABSTRACT FROM AUTHOR]

Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 μM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI50 = 0.7–1.3 μM). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-AblT315I, Bcr-AblE255K, and Bcr-AblY253H point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-AblT315I (GI50 > 20 μM) compared to 11b–f (GI50 = 6.4–11.5 μM). Molecular docking studies explained the structure–activity relationship of these purines in Bcr-AblWT and Bcr-AblT315I. Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells. [ABSTRACT FROM AUTHOR]

Erythroleukemia is a rare form of acute myeloid leukemia (AML). Its molecular pathogenesis remains vague, and this disease has no specific therapeutic treatments. Previously, our group isolated a series of Carbon 21 (C-21) steroidal glycosides with pregnane skeleton from the root of Cynanchum atratum Bunge. Among them, we found that a compound, named BW18, can induce S-phase cell cycle arrest and apoptosis via the mitogen-activated protein kinase (MAPK) pathway in human chronic myeloid leukemia K562 cells. However, its anti-tumor activity against erythroleukemia remains largely unknown. In this study, we aimed to investigate the anti-erythroleukemia activity of BW18 and the underlying molecular mechanisms. Our results demonstrated that BW18 exhibited a good anti-erythroleukemia activity in the human erythroleukemia cell line HEL and an in vivo xenograft mouse model. In addition, BW18 induced cell cycle arrest at the G2/M phase and promoted megakaryocytic and erythroid differentiation in HEL cells. Furthermore, RNA sequencing (RNA-seq) and rescue assay demonstrated that overexpression of platelet-derived growth factor receptor beta (PDGFRB) reversed BW18-induced megakaryocytic differentiation in HEL cells, but not erythroid differentiation. In addition, the network pharmacology analysis, the molecular docking and cellular thermal shift assay (CETSA) revealed that BW18 could inactivate Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, which might mediate BW18-induced erythroid differentiation. Taken together, our findings elucidated a novel role of PDGFRB in regulating erythroleukemia differentiation and highlighted BW18 as an attractive lead compound for erythroleukemia treatment. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome/neoplasm (MDS) comprises a group of heterogeneous hematopoietic disorders that present with genetic mutations and/or cytogenetic changes and, in the advanced stage, exhibit wide-ranging gene hypermethylation. Patients with higher-risk MDS are typically treated with repeated cycles of hypomethylating agents, such as azacitidine. However, some patients fail to respond to this therapy, and fewer than 50% show hematologic improvement. In this context, we focused on the potential use of epigenetic data in clinical management to aid in diagnostic and therapeutic decision-making. First, we used the F-36P MDS cell line to establish an azacitidine-resistant F-36P cell line. We performed expression profiling of azacitidine-resistant and parental F-36P cells and used biological and bioinformatics approaches to analyze candidate azacitidine-resistance-related genes and pathways. Eighty candidate genes were identified and found to encode proteins previously linked to cancer, chronic myeloid leukemia, and transcriptional misregulation in cancer. Interestingly, 24 of the candidate genes had promoter methylation patterns that were inversely correlated with azacitidine resistance, suggesting that DNA methylation status may contribute to azacitidine resistance. In particular, the DNA methylation status and/or mRNA expression levels of the four genes (AMER1, HSPA2, NCX1, and TNFRSF10C) may contribute to the clinical effects of azacitidine in MDS. Our study provides information on azacitidine resistance diagnostic genes in MDS patients, which can be of great help in monitoring the effectiveness of treatment in progressing azacitidine treatment for newly diagnosed MDS patients. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal translocation t(9;22)(q34;q11), in the BCR and ABL genes. These rearrangements in both genes lead to the formation of various fusion mRNA products, with preferential expression of b2a2, b3a2, and other BCR::ABL1 mRNA variants, combined with additional chromosomal abnormalities. Notably, the distribution and frequency of different mRNA variants vary in different populations. However, studies concerning this in Mexico are limited, and the results have been inconclusive. This study therefore aimed to determine the distribution of BCR::ABL1 mRNA variants in different clinical phases of CML and their effect on hematological parameters and patient survival. This study included 33 patients, whose demographic, clinical, and molecular data on BCR::ABL1 mRNA variants and hematological parameters were collected to identify potential associations. A total of 84.8% (n = 28) of patients had BCR::ABL1 translocation and increased platelet and basophil counts. The most frequent mRNA variant was b3a2 (64.3%), followed by b2a2 (28.6%) and e1a2 (3.6%). Concerning the clinical phases of CML, 75.8% (n = 25), 21.2% (n = 7), and 3% (n = 1) of patients were in the chronic, blast, and accelerated phases, respectively. Moreover, the b3a2 mRNA variant was more commonly identified in patients in the chronic phase. No correlation was observed between mRNA variant expression and patient survival. However, b2a2 was indicative of patients with longer survival as well as those treated with imatinib or nilotinib. Additionally, platelet count could be a marker of BCR::ABL1 translocation. [ABSTRACT FROM AUTHOR]

Background and Objectives: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. Material and Methods: We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. Results: The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-β, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. Conclusions: The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed. [ABSTRACT FROM AUTHOR]

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib. [ABSTRACT FROM AUTHOR]

Fiber-reinforced cementitious matrix (FRCM) composites have been largely used to strengthen existing concrete and masonry structures in the last decade. To design FRCM-strengthened members, the provisions of the Italian CNR-DT 215 (2018) or the American ACI 549.4R and 6R (2020) guidelines can be adopted. According to the former, the FRCM effective strain, i.e., the composite strain associated with the loss of composite action, can be obtained by combining the results of direct shear tests on FRCM–substrate joints and of tensile tests on the bare reinforcing textile. According to the latter, the effective strain can be obtained by testing FRCM coupons in tension, using the so-called clevis-grip test set-up. However, the complex bond behavior of the FRCM cannot be fully captured by considering only the effective strain. Thus, a cohesive approach has been used to describe the stress transfer between the composite and the substrate and cohesive material laws (CMLs) with different shapes have been proposed. The determination of the CML associated with a specific FRCM–substrate joint is fundamental to capture the behavior of the FRCM-strengthened member and should be determined based on the results of experimental bond tests. In this paper, a procedure previously proposed by the authors to calibrate the CML from the load response obtained by direct shear tests of FRCM–substrate joints is applied to different FRCM composites. Namely, carbon, AR glass, and PBO FRCMs are considered. The results obtained prove that the procedure allows to estimate the CML and to associate the idealized load response of a specific type of FRCM to the corresponding CML. The estimated CML can be used to determine the onset of debonding in FRCM–substrate joints, the crack number and spacing in FRCM coupons, and the locations where debonding occurs in FRCM-strengthened members. [ABSTRACT FROM AUTHOR]

BCR-ABL tyrosine kinase inhibitors (TKIs) are effective drugs in the treatment of patients with chronic myeloid leukemia. However, based on clinical studies, ponatinib was associated with the development of thrombotic complications. Since endothelial cells (ECs) regulate blood coagulation, their abnormal phenotype may play a role in the development of thrombotic events. We here aimed to investigate the effect of ponatinib on the procoagulant activity of cultured endothelial cells in vitro. Human coronary artery endothelial cells (HCAECs) were incubated with 50, 150, and 1000 nM of ponatinib. Subsequently, phosphatidylserine (PS) exposure and endothelial microvesicles (EMVs) were measured by flow cytometry. In addition, EC- and EMV-dependent thrombin generation was analyzed. To investigate pro-apoptotic effects of ponatinib, the level of Bax and Bcl-xL proteins were studied using Western blot and F3, THBD, and VCAM1 mRNAs were quantified by qPCR. Therapeutic concentrations of ponatinib significantly increased PS expression on ECs and the amount of EMVs which significantly shortened the time parameters of thrombin generation. In addition, these changes were associated with an increased ratio of Bax and Bcl-xL proteins in the presence of the decreased THBD mRNA level. Overall, ponatinib enhances the procoagulant activity of ECs via inducing apoptosis, which may contribute to thrombotic events. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML. [ABSTRACT FROM AUTHOR]

The management of chronic myelogenous leukemia (CML) has seen significant progress with the introduction of tyrosine kinase inhibitors (TKIs), particularly Imatinib. However, a notable proportion of CML patients develop resistance to Imatinib, often due to the persistence of leukemia stem cells and resistance mechanisms independent of BCR::ABL1 This study investigates the roles of IL6R, IL7R, and MYC in Imatinib resistance by employing CRISPR/Cas9 for gene editing and the Non-Invasive Apoptosis Detection Sensor version 2 (NIADS v2) for apoptosis assessment. The results indicate that Imatinib-resistant K562 cells (K562-IR) predominantly express IL6R, IL7R, and MYC, with IL6R and MYC playing crucial roles in cell survival and sensitivity to Imatinib. Conversely, IL7R does not significantly impact cytotoxicity, either alone or in combination with Imatinib. Further genetic editing experiments confirm the protective functions of IL6R and MYC in K562-IR cells, suggesting their potential as therapeutic targets for overcoming Imatinib resistance in CML. This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options. [ABSTRACT FROM AUTHOR]

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells. Additionally, oxidative stress and reactive oxygen species generation also mediate apoptosis through genomic activation. Furthermore, it was shown that oxidative stress has a role in both BCR-ABL-independent and BCR-ABL-dependent resistance pathways to tyrosine kinases, while patients with chronic myeloid leukemia were found to have a significantly reduced antioxidant level. The ideal environment for tyrosine kinase inhibitor therapy is produced by a favorable oxidative status. We discuss the latest studies that aim to manipulate the redox system to alter the apoptosis of cancerous cells. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article. [ABSTRACT FROM AUTHOR]