Treatment Of Chronic Myeloid Leukemia Research Articles

Impact of First- and Second-Generation Tyrosine Kinase Inhibitors on the Development of Graft-Versus-Host Disease in Individuals with Chronic Myeloid Leukemia: A Retrospective Analysis on Behalf of the Polish Adult Leukemia Group

Background: The implementation of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has brought a significant improvement in the prognosis for CML patients and a decrease in the number of patients requiring allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, the impact of TKIs on allo-HCT outcomes has not been thoroughly explored. Objectives: The main endpoint of our research was to assess the impact of prior TKI treatment on acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD). Methods: In our retrospective analysis, we included 240 patients treated between 1993 and 2013 and divided them into three groups according to the therapy administered prior to haploidentical, matched-related, or matched-unrelated donor allo-HCT (imatinib group n = 41, dasatinib/nilotinib group n = 28, TKI-naïve group n = 171). Results: Both the cumulative incidence of aGvHD (p = 0.044) and cGvHD (p < 0.001) in individuals receiving second-generation TKIs (2G-TKIs) prior to allo-HCT were decreased compared to patients receiving no TKIs or imatinib (IMA) (40.7% vs. 61.4% vs. 70.7%, p = 0.044; 25.0% vs. 76.4% vs. 51.2%, p < 0.001, respectively). In the case of the 2G-TKI cohort, the number of low-grade aGvHD and cGvHD was significantly lower compared to the IMA and TKI-naïve groups (p = 0.018, p = 0.004; p < 0.001 versus TKI-naïve, respectively). In terms of 3-year overall survival (OS), there were no important variations between TKI-naïve, IMA, and 2G-TKI (55% vs. 49.9% vs. 69.6%, p = 0.740). Conclusions: The results of our study suggest that TKI treatment prior to allo-HCT may have a protective impact on immune-mediated outcomes.

N-Degron PROTACs as a Potential Therapeutic Approach for Chronic Myeloid Leukemia.

Many oncoproteins are important therapeutic targets because of their critical role in inducing rapid cell proliferation, which represents one of the salient hallmarks of cancer. Chronic Myeloid Leukemia (CML) is a cancer of hematopoietic stem cells that is caused by the oncogene BCR-ABL1. BCR-ABL1 encodes a constitutively active tyrosine kinase protein that leads to the uncontrolled proliferation of myeloid cells, which is a hallmark of CML. A current therapeutic approach for the treatment of CML, Tyrosine Kinase Inhibitors (TKIs), effectively inactivates BCR-ABL1 kinase activity; however, drug resistance to TKIs limits the long-term potential for this treatment. Proteolysis Targeting Chimera (PROTAC) has emerged as a promising pharmacological approach for degrading, rather than inhibiting, targeted proteins by harnessing the ubiquitin-proteosome system. This process involves tagging a Protein of Interest (POI) with ubiquitin by the E3 ubiquitin ligases, which subsequently target the protein for proteasomal degradation. The N-end rule or the N-degron concept describes the correlation between the metabolic stability of a protein and the biochemical identity of its N-terminal amino acid. A recent work unveiled that N-degron PROTACs could offer a potential treatment for CML by targeting and degrading BCR-ABL1 proteins. Herein, we present the molecular and biochemical implications for targeting chronic myeloid leukemia.

Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms.

Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18th edition of the workshop and includes reference to some data presented or published after the workshop, including the 26th John Goldman CML conference.

A Cr2AlC MAX Phase‐Based Electrochemical Probe for the Detection of Asciminib in Biological and Pharmaceutical Samples

AbstractThe Cr2AlC MAX phase, a two‐dimensional transition metal carbide, offers a compelling combination of properties ideal for electrochemical sensor fabrication. The exceptional electrical conductivity, high surface area, and inherent electrocatalytic activity of the catalyst enable the sensitive and selective detection of diverse analytes, including biomolecules of critical clinical relevance. This work presents the construction of a novel electrochemical sensor featuring a nanoscale Cr2AlC MAX phase‐modified electrode, demonstrating its exceptional analytical performance in Asciminib detection, a crucial aspect of chronic myeloid leukemia (CML) treatment. The sensor exhibits a low limit of detection (0.212 µM) and a low limit of quantification (0.698 µM) and demonstrates excellent sensitivity toward Asciminib in the linear range of 1 µM–10 µM. Moreover, a rigorous tolerance limit has been established, allowing the sensor to tolerate the highest concentration of interfering substances with an error of less than ± 5% in determining ASC current. Successful quantification of Asciminibin biological samples further validates the method's reliability for real‐world applications. This novel electrochemical approach provides a rapid and cost‐effective alternative to existing methods and contributes significantly to the nanomaterial‐enabled advancement of CML management, ensuring precise Asciminib quantification at the nanoscale.

Caught in the Crossfire: Unmasking the Silent Renal Threats of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Renal adverse drug reactions (ADRs) associated with tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) are relatively rare, and there is currently no standardized protocol for their management. Therefore, this study aimed to summarize renal ADRs related to TKIs use in CML and propose an evidence-based approach to monitor and manage these ADRs. A systematic literature review was performed to identify renal ADRs associated with TKIs in CML. Two authors screened the search results and extracted data from 37 eligible studies. These findings were then used to develop a scheme for clinicians to monitor and manage these ADRs. Overall, imatinib seemed to be significantly linked to renal adverse events compared to other TKIs, and switching to dasatinib or nilotinib significantly improved renal function. Similar events were reported with bosutinib, although they were not statistically significant. However, most of the renal events reported on dasatinib were described as nephrotic syndrome that resolved with switching to imatinib. Few cases were reported with nilotinib that described tumor lysis syndrome (TLS)-related kidney injury. Recommendations include monitoring for progressive decline in the estimated glomerular filtration rate with imatinib, nephrotic syndrome with dasatinib, and TLS with nilotinib. Additionally, holding the offending TKI and managing renal ADRs according to local guidelines were adopted more frequently than reducing the TKI dose.

Genetic diversity and variation in chronic myeloid leukemia patients of Indian origin- Implications for treatment response and prognosis

Chronic myeloid leukemia (CML) is a prevalent blood malignancy characterized by the breakpoint cluster region - abelson tyrosine kinase gene translocation (BCR-ABL1) fusion gene. In India, CML accounts for a significant portion of adult leukemias, with a notable male preponderance and an increasing trend in young adult patients. Most patients present in the chronic phase, and the Sokal/European treatment and outcome study score (EUTOS)/Hasford scoring systems may be used for risk stratification. The advent of imatinib revolutionized CML treatment, making it more accessible, although challenges such as intolerance and treatment failure persist. Cytogenetic analysis is essential for diagnosis and monitoring, with molecular assessments indicating treatment response. Compliance plays a crucial role in achieving optimal outcomes, with non-adherence associated with poorer prognosis. Mutational analysis aids in treatment decisions for patients with suboptimal response to tyrosine kinase inhibitors, revealing resistance patterns. Toxicity profiles resemble Western data, with anemia being the most common hematological toxicity. Despite limitations in resources and late presentations, Indian CML outcomes mirror Western standards, highlighting the importance of standardized cytogenetic testing for improved clinical outcomes.

The cost-effectiveness of chronic myeloid leukemia treatment strategies in the Indian healthcare context

The cost-effectiveness of chronic myeloid leukemia treatment strategies in the Indian healthcare context

Design, <i>In Silico</i> Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to Bcr-Abl Tyrosine Kinase

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is currently still an unmet need for effective and safe drugs to treat patients with resistance and intolerance to clinically used drugs. In this work, 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid were designed followed by in silico assessment of the inhibitory potential of these compounds against Bcr-Abl tyrosine kinase and determination of their antitumor activity on cell models of the K562 (chronic myeloid leukemia), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) lines. As a result of the joint analysis of computational and experimental data, three compounds exhibiting antitumor activity against cells of the K562 and HL-60 lines were identified. A lead compound demonstrating effective inhibition of the growth of these cells was found, as evidenced by the low values of IC50 equal to 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The results obtained indicate that the identified compounds form good scaffolds for the design of novel, effective and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.

Pharmacokinetic Interaction between Imatinib and Tacrolimus in Rats

Objective: Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats. Methods: Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and Ndesmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry. Results: After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and Cmax of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and Cmax of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC0-24 and AUC0-∞ of tacrolimus (P < 0.05). Conclusion: Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.

Zinc oxide fabricated by rutin as potent anti-leukemia nanostructure.

Treatment of chronic myeloid leukemia (CML) is a significant therapeutic challenge, and exploration of novel treatment approaches is an urgent necessity. This work investigates the anticancer properties of rutin-conjugated zinc oxide nanoparticles (Rut-ZnO NPs) against CML cells. Physicochemical properties of the NPs were studied by FT-IR, FE-SEM, XRD, zeta potential, and DLS analyses. The MTT, flow cytometry, and quantitative PCR assays were utilized to evaluate cell viability, apoptosis, and Bax/Bcl-2 ratio, respectively. The ZnO-Rut NPs were amorphous with an average size of 59.50nm, and hydrodynamic size and zeta potential were 161.7nm and -34.3 mV, respectively. The ZnO-Rut NPs showed good cytocompatibility as the viability of peripheral blood mononuclear cells remained above 85% at concentrations up to 100μg/mL. ZnO-Rut NPs reduced the viability of K562 cells from 92 to 31% at exposure concentrations from 3.125 to 400μg/mL. The IC50 values for rutin, ZnO NPs, and ZnO-Rutin NPs against K562 cells were 501.8, 386.3, and 175.9μg/mL, respectively. Following the exposure to ZnO-Rutin NPs, the percentage of early apoptosis increased slightly from 10.5% to 14.1%, and a significant increase (from 11% to 50.9%) in late apoptosis was observed. The mRNA level of the Bax elevated to 1.98 folds, and the Bcl-2 gene was downregulated to 0.33 folds, underscoring the mechanism by which ZnO-Rutin NPs promote apoptosis. This study highlights the efficient anticancer potential of ZnO-Rutin NPs against CML cells, providing the basis for further investigations into their clinical applicability and underlying mechanisms of action.

Chiglitazar diminishes the warburg effect through PPARγ/mTOR/PKM2 and increases the sensitivity of imatinib in chronic myeloid leukemia

BackgroundA tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, the emergence of IM resistance presents a significant challenge to disease management. A characteristic of cancer cells, including IM-resistant CMLs, are characterized by heightened uptake of glucose and aberrant glycolysis in the cytosol, which is known as the Warburg effect. In addition to its potential to modulate the Warburg effect, Chiglitazar (Chi), a compound that regulates glucose metabolism, has also been investigated for its implication in cancer treatment. This suggests that combining Chi with IM may be a therapeutic strategy for overcoming IM resistance in CML.MethodsSensitive and IM-resistance CML cells were treated with Chi in vitro, followed by detecting of extracellular acidification rate (ECAR) using a Seahorse XF Analyzer. CML cell proliferation, cell cycle distribution, and apoptosis were tested by CCK-8 assay and flow cytometry. RNA sequencing was utilized to investigate potential transcriptional changes induced by Chi usage. In vivo studies were conducted on immunodeficient mice implanted with CML cells and given Chi and/or IM later. Tumor growth was monitored, as well as tumor burden and survival rates between groups.ResultsOur metabonomic, transcriptomic, and molecular biology studies demonstrated that Chi, in part, diminished the Warburg effect by reducing glucose and lactate production in imatinib-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. This modulation of glucose metabolism resulted in reduced cell proliferation and enhanced sensitivity to IM in imatinib-resistant CML cells in vitro. Rescue assay by introducing shPPARγ or mTOR activator verified the underlying regulatory pathway. Also, the combination of Chi and IM synergistically increased the sensitivity of IM in vivo and prolonged the survival of imatinib-resistance CML transplanted mice.ConclusionsOur results demonstrated the potential of Chi to overcome IM resistance in vitro and in vivo. By inhibiting the Warburg effect through the PPARγ/mTOR/PKM2 pathway, Chi resensitizes CML cells towards imatinib treatment. Combining IM with Chi is an alternative therapeutic option for CML management, especially for IM-resistant CML patients.

Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis.

Tyrosine kinase inhibitors (TKIs) have markedly improved the overall survival rate of patients with chronic myeloid leukemia (CML), enabling them to achieve a normal life expectancy. However, toxicity, relapse, and drug resistance continue to pose major challenges in the clinical treatment of CML. The progression of leukemia is directly connected to higher expression levels and enzymatic actions of matrix metalloproteinase-2 (MMP-2). It is also associated with increased expression and enzymatic actions of matrix metalloproteinase-9 (MMP-9). From this perspective, MMP-2 and MMP-9 offers a promising strategy for developing novel therapeutic molecules that could be effective in treating CML. This study is the Part-III of D(-)-glutamine-based MMP-2 inhibitors series for the management of chronic myeloid leukemia. Fourteen newly synthesized p-tosyl-D(-)-glutamine derivatives were examined in cell culture-based antileukemic assays and also evaluated for their ability to inhibit MMPs. The lead compounds 5g and 5j demonstrated the most promising antileukemic potential. Compounds 5g and 5j are safe for normal cells and effectively block gelatinases (MMP-2 and MMP-9). The best active molecule 5g induced significant apoptosis. Compound 5g reduced MMP-2 levels in the K562 cell line. It also had strong antiangiogenic effects in the ACHN cell line. The strongest MMP-2 inhibitor, 5g, had stable binding at the MMP-2 active site, which is linked to its effective inhibition of MMP-2. In conclusion, these p-tosyl-D(-)-glutamine derivatives are promising MMP-2 inhibitors. They have strong anti-CML effects and should be studied more for future CML treatment.

Results of various somatic mutations detection in patients with chronic myeloid leukemia

Background. Somatic mutations in chronic myeloid leukemia (CML) patients are considered as possible factors for the failure of tyrosine kinase inhibitor (TKI) therapy, and the study of their characteristics is of interest.Aim. To evaluate the genetic profile of blood cells in CML patients using nextgeneration sequencing.Materials and methods. Retrospective study was conducted in two groups of patients: group 1 with TKI therapy failure (n = 29) and group 2 with optimal response to TKI therapy (n = 29). The target panel for nextgeneration sequencing included 19 genes: ASXL1, DNMT3A, FLT3, IDH1, IDH2, NPM1, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF2, KIT, WT1, CEBPA, ZRSR2, JAK2, GATA2, ABL1. In order to assess clonal evolution, additional samples were examined at a retrospective point in time closest to the primary CML diagnosis.Results. In group 1, mutations in 8 genes (including ABL1) were identified in 19/29 (66 %) patients. Excluding ABL1, mutations were identified in 15 (52 %) patients. In 9 (31 %) patients, >1 mutation (2 to 4) was detected. Frequency of genes mutations in group 1: ABL1 in 11 (38 %) patients, ASXL1 in 9 (31 %) patients, DNMT3A in 3 (10 %) patients, RUNX1, CEBPA in 2 patients (7 %), WT1, NPM1, TET2 in 1 patient (3.5 %). In 7 (24 %) patients there was a combination of mutations in ABL1 gene and in another gene; the most frequent combination of mutations in genes: ABL1 + ASXL1 – in 4 patients (14 %). The dynamics of mutant clones in group 1 was evaluated in 21/29 (72 %) patients. In 10/21 (48 %) patients somatic mutations in genes appeared during CML treatment, in 14/21 (67 %) patients previously detected mutations persisted, in 1 (5 %) the mutation disappeared. In group 2, somatic mutations were detected in 2/29 (7 %) patients: in DNMT3A (ariant Allele Frequency (AF) 5 %) and TP53 (AF 9 %) genes – these mutations were not detected at the diagnosis of CML. In one patient ASXL1 mutation (AF 5 %) was detected only at diagnosis, and was not detected subsequently with optimal response to therapy.Conclusion. The presence of somatic gene mutations is associated with a resistant CML course: somatic mutations in genes other than ABL1 were more common in CML patients with TKI therapy failure than in those with optimal response: 52 % vs. 7 % (p ≤0.05). Mutations in ASXL1 (31 %) and DNMT3A (10 %) were the most frequently detected. The frequency of ABL1 and ASXL1 mutations combination amounted to 14 %. uring followup, somatic mutations predominantly persisted or appeared over time in CML patients with TKI therapy resistance.

EE119 Cost Effectiveness of Asciminib for the Post 2 Tyrosine Kinase Inhibitor Treatment of Chronic Phase Chronic Myeloid Leukaemia in Türkiye

EE119 Cost Effectiveness of Asciminib for the Post 2 Tyrosine Kinase Inhibitor Treatment of Chronic Phase Chronic Myeloid Leukaemia in Türkiye

Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells.

Dasatinib is a second-generation breakpoint cluster region-abelson 1 (BCR::ABL1) tyrosine kinase inhibitor (TKI) used for the treatment of chronic myeloid leukemia (CML). Overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) in CML cells contributes to dasatinib resistance and poor chemotherapeutic responses. Considering that the xanthine oxidase inhibitor febuxostat has anti-ABCG2 activity, febuxostat may enhance the efficacy of dasatinib. However, the mechanism of action of febuxostat and its effects on the efficacy and safety of dasatinib in patients with CML are unknown. Therefore, this study aimed to retrospectively investigate the clinical impact of concomitant febuxostat on the efficacy of dasatinib in 65 patients with CML. Moreover, its underlying mechanism was explored in vitro using an ABCG2-overexpressing CML cell line (K562-ABCG2 cells). The retrospective study revealed that the achievement ratios of early molecular response at three months and major molecular response at 12 months after dasatinib treatment in patients with febuxostat were significantly higher than those in patients without febuxostat (91 % vs. 70 %, p = 0.034, 86 % vs. 53 %, p = 0.013, respectively). In vitro studies showed that febuxostat significantly decreased cell viability and increased the residual dasatinib concentration in dasatinib-treated K562-ABCG2 cells. Moreover, phosphorylated BCR::ABL1 levels in dasatinib-treated K562-ABCG2 cells were significantly decreased by febuxostat. Overall, concomitant febuxostat enhanced the efficacy of dasatinib in patients with CML. This was achieved partially by inhibition of ABCG2-mediated excretion of dasatinib from CML cells. Therefore, these findings provide important insights for improving CML treatment and overcoming TKI resistance.

Synergistic Effects of Inecalcitol With Imatinib and Dasatinib on Chronic Myeloid Leukemia Cell Lines.

According to American Cancer Society's recent estimates, about 5,330 men and 3,950 women are diagnosed each year with chronic myeloid leukemia (CML). Roughly, 750 men and 530 women are predicted to die as a result of CML, establishing a dire need for advancements in CML treatment. Tyrosine kinase inhibitors (TKIs) imatinib and dasatinib have profound effects for prognosis and delaying survival from CML. The role of inecalcitol in the treatment and prevention of various cancers including leukemia has been established. The aim of this study was to analyze the putative synergistic treatment effects of inecalcitol in combination with imatinib or dasatinib on various cell lines including AR-230, LAMA-84-s, KCL-22, and U-937. Cells grown in plates were treated alone or with varying combinations of inecalcitol, imatinib, and dasatinib and incubated for 48 h at 37°C. Cell death was determined using MTT assay. KCL-22 and U-937 were resistant to both combination treatments, whereas AR-230 exhibited a maximal antiproliferative effect (24%) with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.001). With dasatinib (0.456 nM) and inecalcitol (15.8 μM), AR-230 exhibited a 34% antiproliferative effect (p<0.001). In drastic contrast, LAMA84-s exhibited a 45% antiproliferative effect (with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.006). Notably, with dasatinib (0.456 nM) and inecalcitol (15.8 μM), LAMA84-s exhibited approximately 78% cell killing (p<0.007). The study suggests that the synergistic effects of inecalcitol with imatinib on cell killing are more drastic in some cells than others. These varying effects may be due to differences in cell metabolism.

EE463 Cost of Chronic Myeloid Leukaemia Treatment in Türkiye: Results of a Delphi Panel Approach

EE463 Cost of Chronic Myeloid Leukaemia Treatment in Türkiye: Results of a Delphi Panel Approach

Hyperoside induces ferroptosis in chronic myeloid leukemia cells by targeting NRF2

BackgroundHyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside compound derived from plants in the Hypericum and Crataegus genera that reportedly exhibits an array of anti-inflammatory, antioxidant, and antitumor properties such that it has been used to treat various diseases. Whether it can serve as an effective treatment for chronic myeloid leukemia (CML) cells, however, has yet to be established. The present study was thus devised to assess the therapeutic effects of hyperoside on CML cells and to clarify the underlying mechanism of action.MethodsCellular viability, proliferative activity, migration, and apoptotic death were respectively analyzed through CCK-8, EDU, transwell, and flow cytometry assays. RNA-seq and bioinformatics approaches were further employed to evaluate the mechanisms through which hyperoside influences CML cells, while analyses of reactive oxygen species (ROS) and free iron were detected with commercial kits. Transmission electron microscopy was used to assess mitochondrial morphology. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) approaches were also used to explore the ability of hyperoside to target NRF2.ResultsFrom a mechanistic perspective, hyperoside was able to inhibit SLC7A11/GPX4 signaling in a manner that was abrogated by the ferroptosis inhibitor ferrostatin-1. NRF2 was also closely associated with the inactivation of the SLC7A11/GPX4 axis mediated by hyperoside such that overexpressing NRF2 ablated the benefits associated with hyperoside treatment.ConclusionsThe present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death.

Role of MicroRNAs in Chronic Myeloid Leukemia (CML) Treatment, Biomarkers, and Resistance to Tyrosine Kinase Inhibitor: A Bioinformatics-Based Analysis

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the reciprocal translocation of the BCR-ABL1 oncogene, which activates tyrosine kinase resulting in uncontrolled cell proliferation and apoptosis suppression. Although Imatinib (IM) is an effective treatment, IM resistance remains a significant concern. Therefore, microRNAs (miRNAs) have emerged as potential alternative therapies. These short, non-coding RNAs (20-22 nucleotides) regulate gene expression by binding to the 3' untranslated region (3'UTR) of target genes. The study aims to identify miRNAs linked to CML, determine miRNA’s target genes, construct a protein-protein interaction (PPI) network, and analyze pathways and gene ontology. A literature search using the keywords “microRNA”, and “chronic myeloid leukemia” yielded relevant papers, which were screened and categorized into three groups: 1) miRNA associated with TKI resistance, 2) miRNA as biomarkers or leukemogenesis, and 3) miRNA as therapy. Target genes for the identified miRNAs were determined using DIANA tools and miRTarBase. Gene ontology and pathway analysis were conducted using DAVID, while PPI and network visualization were performed using STRING, Cytoscape, and ClueGO. Thirteen miRNAs were selected, targeting 782 genes and forming 16 clusters. ClueGO identified clusters associated with key biological processes, including G1/S cell cycle transition, miRNA-mediated gene silencing, hematopoietic stem cell differentiation, and apoptosis regulation. Target genes are also significant in the CML pathway and other cancer pathways, such as p53, ErbB, FoxO, autophagy, apoptosis, VEGF, TNF, and microRNA. Notably, hsa-miR-16 emerged as the most promising therapeutic and biomarker candidate for CML, highlighting its role in critical pathways.

COVID-19 mitigates the response to TKIs in patients with CML via the inhibition of T-cell immunity.

Chronic myeloid leukemia (CML) is a severe hematological malignancy characterized by BCR-ABL fusion gene. The advent of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL has improved the landscape of CML treatment dramatically. The occurrence of coronavirus disease 2019 (COVID-19) has challenged many cancers. However, its effect on TKI therapy of CML remains unknown. In this study, we collected peripheral blood from chronic phase CML patients treated with TKIs at low-level BCR-ABL P210 during COVID-19 pandemic, and determined the alterations of BCR-ABL P210 by applying the well-established BCR-ABL P210 detection system. Our results showed that the level of BCR-ABL P210 of CML patients was significantly elevated shortly after contracting COVID-19, and then recovered to pre-infection level within one month. The elevated degree of P210 was positively correlated with the duration of COVID-19. And the level of P210 was elevated in CML patients that took COVID-19 vaccination. Furthermore, lymphocyte subsets and cytokine detections were performed by flow cytometry to analyze the alteration of immune responses. Our results showed that effector CD8+ T (Teff) cells were significantly downregulated while naïve CD8+ T cells or Treg cells were obviously upregulated in P210-elevated CML patients after contracting COVID-19 compared to that in P210-unchanged or decreased CML patients. Moreover, the SARS-CoV-2 pseudovirus was constructed to further determine its effects. The results showed that the level of BCR-ABL P210 was upregulated upon transfection of SARS-CoV-2 pseudovirus into blood samples of CML patients. Our results demonstrate that COVID-19 suppresses the immune activity and consequentially elevates the level of BCR-ABL P210 of CML patients.