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Primary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Crisis Blástica , Resistencia a Antineoplásicos/genéticaRESUMEN
INTRODUCTION: A high incidence of mortality and severe COVID-19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID-19 pandemic; however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID-19 vaccinations in subsequent pandemic waves may modify COVID-19 disease severity and mortality in this immunocompromised population. We describe COVID-19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS-CoV-2 delta and omicron variants. METHODS: We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS-CoV-2 from May 2021 to May 2022. Descriptive statistics were reported; the chi-square test was utilized to identify factors associated with 90-day all-cause mortality and severity of COVID-19 infection. RESULTS: Over the 1-year study period, 77 HSCT recipients at our center contracted COVID-19 (43 allogenic; 34 autologous). Twenty-six (33.8%) patients were infected with the SARS-CoV-2 delta variant, while 51 (66.2%) had the SARS-CoV-2 omicron variant. Thirty-nine (50.6%) patients required hospitalization. More than 80% had received prior COVID-19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID-19 infection was associated with increased odds of mortality [odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20-40]. The 90-day all-cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01-0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01-0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10-23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89-75.4) were associated with greater severity of COVID-19 infection. CONCLUSION: We observed favorable outcomes with COVID-19 infection in a cohort of vaccinated HSCT patients. The SARS-CoV-2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID-19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID-19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS-CoV-2 variants also remains important in this immunocompromised population.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Vacunas contra la COVID-19 , Pandemias , Estudios Retrospectivos , Receptores de Trasplantes , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND: Approximately 30-70% of patients who have undergone allogeneic (allo) hematopoietic stem cell transplantation (HSCT) eventually experience chronic graft-versus-host disease (cGVHD). Patients who develop steroid-refractory (SR)-cGVHD are the most severely impacted due to significant disease and financial burden. There remains an unmet need for safe, efficacious, and accessible treatments for these patients. The objective of this study was to determine the cost effectiveness of ruxolitinib for treatment of SR-cGvHD from the Singapore healthcare system perspective. METHODS: Based on data from the REACH3 randomized open-label trial, a semi-Markov model was developed to evaluate cost-effectiveness of ruxolitinib compared with investigators' choice of best alternative therapy (BAT) for treatment of patients > 12 years of age with SR-cGVHD in Singapore over a 40-year time horizon. The model only considered direct medical-care costs related to the treatment of SR-cGVHD and reported them in Singapore Dollars (SGD). Half-cycle correction was applied to all costs and outcomes, which were discounted at 3%. Probabilistic sensitivity analysis (PSA), one-way sensitivity analysis (OWSA), and scenario analysis were conducted to explore the drivers of uncertainty in the model. RESULTS: In the deterministic base case, more life years (LY; 10.28 vs. 9.42) and quality-adjusted life years (QALYs; 7.31 vs. 6.51) were gained with ruxolitinib than BAT at higher costs (SGD 303,214 vs. SGD 302,673) leading to an incremental cost-effectiveness ratio (ICER) of SGD 677/QALY. At a willingness-to-pay threshold of SGD 75,000/QALY gained, PSA found that ruxolitinib had a 78.52% probability of being cost-effective. Findings were sensitive to variations in non-responder utilities in the BAT arm and duration of BAT treatment in the OWSA, or comparison to either methotrexate (MTX) or mycophenolic acid as a single comparator in the scenario analysis. ICERs remained lower than SGD 75,000/QALY in all other tested variations and scenarios. CONCLUSION: Ruxolitinib is likely to be cost-effective from Singapore healthcare system's perspective for patients with SR-cGVHD, which is promising in the management of patients with unmet clinical needs.
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Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.
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Anticuerpos Monoclonales Humanizados , Hemoglobinuria Paroxística , Femenino , Humanos , Masculino , Embarazo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inactivadores del Complemento/uso terapéutico , Consenso , Técnica Delphi , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/terapia , Complicaciones Hematológicas del Embarazo/diagnóstico , Complicaciones Hematológicas del Embarazo/terapia , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , SingapurRESUMEN
INTRODUCTION: To profile conjunctival T cell populations in allogeneic hematopoietic stem cell transplant (HSCT) patients after instillation of daily topical cyclosporine-A (CsA) 0.1% cationic emulsion (Ikervis), and to evaluate patients' tolerance to these eye drops. METHODS: Nineteen participants were prescribed Ikervis prophylaxis once daily to both eyes from 3-5 weeks pre-HSCT to 12 months post-HSCT. The outcome measure was conjunctival T cell proportions from flow cytometry after impression cytology. Covariates included visual acuity, intraocular pressure, slit lamp and fundal examination, dry eye (SPEED) and quality of life questionnaires, non-invasive keratograph tear break-up time (NIKBUT), conjunctival redness, meibography, lipid thickness, Schirmer test, tear cytokines, fluorescein staining, tear osmolarity, and meibomian gland expressibility. RESULTS: The conjunctival T cell analysis showed either stable or decreased proportions of conjunctival CD4 T cells at the last visit from baseline in compliant patients. CD4 proportions were increased in non-compliant patients and in the single patient who developed ocular graft-versus-host disease (GVHD). All patients were tolerant to Ikervis but 6/19 were not compliant. In the majority of patients, vision did not affect activities of daily living. Pre- and post-HSCT up to the last study visit, there was no statistically significant change in clinical covariates. Only one participant developed ocular GVHD at 9 months post-HSCT. CONCLUSION: Superficial conjunctival T cell profile reflects compliance to daily topical Ikervis eye drops and clinical ocular surface parameters in allogenic HSCT patients. Tolerance is comparable to other formulations of topical CsA in the first 12 months. GOV IDENTIFIER: NCT04636918. URL: https://clinicaltrials.gov/ct2/show/NCT04636918?cond=ocular+Graft+Versus+Host+Disease&cntry=SG&draw=2&rank=2 .
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Anticoagulantes/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Heparina/efectos adversos , Rivaroxabán/uso terapéutico , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trombocitopenia/diagnósticoRESUMEN
We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.
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Leucemia Mieloide Aguda , Sirtuinas , Apoptosis , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Lisina/metabolismo , Mitocondrias/genética , Fosforilación Oxidativa , Sirtuinas/genéticaRESUMEN
Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI resistance. Among extrinsic factors, cytokine-mediated TKI resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34+ chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34+ CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1 were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34+ CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data support an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.
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Médula Ósea/patología , Citocinas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células Madre Neoplásicas/patología , Factores de Empalme Serina-Arginina/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Factores de Empalme Serina-Arginina/genética , Células Tumorales CultivadasRESUMEN
Despite the efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in chronic phase-chronic myeloid leukemia, the management of blast phase-chronic myeloid leukemia (BP-CML) remains a challenge. Therefore, there is an urgent need to identify alternative agents that act synergistically with BCR-ABL TKIs in BP-CML. Our results show that the anti-malarial agent, mefloquine augments the efficacy of TKIs in CML cell lines and primary CML cells in vitro, including those with the T315I mutation. This effect is selective as mefloquine is more effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells derived from TKI-resistant BP-CML patients than normal cord blood (CB) CD34+ stem/progenitor cells. Notably, the combination of mefloquine and TKIs at sublethal concentrations leads to synergistic effects in CML CD34+ cells, while sparing normal CB CD34+ cells. We further demonstrate that the initial action of mefloquine in CML cells is to increase lysosomal biogenesis and activation, followed by oxidative stress, lysosomal lipid damage and functional impairment. Taken together, our work elucidates that mefloquine selectively augments the effects of TKIs in CML stem/progenitor cells by inducing lysosomal dysfunction.
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Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm of older individuals characterized by persistent monocytosis. Somatic mutations in CMML are heterogeneous and only partially explain the variability in clinical outcomes. Recent data suggest that cardiovascular morbidity is increased in CMML and contributes to reduced survival. Clonal hematopoiesis of indeterminate potential (CHIP), the presence of mutated blood cells in hematologically normal individuals, is a precursor of age-related myeloid neoplasms and associated with increased cardiovascular risk. To isolate CMML-specific alterations from those related to aging, we performed RNA sequencing and DNA methylation profiling on purified monocytes from CMML patients and from age-matched (old) and young healthy controls. We found that the transcriptional signature of CMML monocytes is highly proinflammatory, with upregulation of multiple inflammatory pathways, including tumor necrosis factor and interleukin (IL)-6 and -17 signaling, whereas age per se does not significantly contribute to this pattern. We observed no consistent correlations between aberrant gene expression and CpG island methylation, suggesting that proinflammatory signaling in CMML monocytes is governed by multiple and complex regulatory mechanisms. We propose that proinflammatory monocytes contribute to cardiovascular morbidity in CMML patients and promote progression by selection of mutated cell clones. Our data raise questions of whether asymptomatic patients with CMML benefit from monocyte-depleting or anti-inflammatory therapies.
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Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Monocitos/metabolismo , Monocitos/patología , Transcriptoma , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios de Casos y Controles , Biología Computacional/métodos , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Mediadores de Inflamación , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
PURPOSE: Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis. EXPERIMENTAL DESIGN: A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear-cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor). RESULTS: JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo. CONCLUSIONS: Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
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Núcleo Celular/metabolismo , Citoplasma/metabolismo , Mielofibrosis Primaria/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Biomarcadores , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Biología Computacional/métodos , Citoplasma/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Quinasas Janus/genética , Quinasas Janus/metabolismo , Ratones , Terapia Molecular Dirigida , Mutación , Trastornos Mieloproliferativos/etiología , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/etiología , Factores de Transcripción STAT/metabolismo , TranscriptomaRESUMEN
BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Niacinamida/análogos & derivados , Pirazoles/farmacología , Piridazinas/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sitios de Unión/efectos de los fármacos , Sitios de Unión/genética , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Terapia Molecular Dirigida/métodos , Mutación , Niacinamida/farmacología , Niacinamida/uso terapéutico , Cultivo Primario de Células , Pirazoles/uso terapéutico , Piridazinas/uso terapéuticoRESUMEN
The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibits tumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/ß-catenin signalling pathway via activation of casein kinase 1α , we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Mitocondrias/metabolismo , Compuestos de Pirvinio/administración & dosificación , Adenosina Trifosfato/química , Animales , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Crisis Blástica/metabolismo , Quinasa de la Caseína I/metabolismo , Línea Celular Tumoral , Proliferación Celular , Dasatinib/administración & dosificación , Dasatinib/uso terapéutico , Humanos , Concentración 50 Inhibidora , Células K562 , Ratones , Ratones SCID , Trasplante de Neoplasias , Fosforilación , Compuestos de Pirvinio/uso terapéutico , Interferencia de ARN , beta Catenina/metabolismoAsunto(s)
Transporte Activo de Núcleo Celular/efectos de los fármacos , Antineoplásicos/farmacología , Hidrazinas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Triazoles/farmacología , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Fusión bcr-abl , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Mesilato de Imatinib/farmacología , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Antineoplásicos/uso terapéutico , Proteína 11 Similar a Bcl2/genética , Biomarcadores de Tumor/genética , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Valor Predictivo de las Pruebas , Pronóstico , Eliminación de Secuencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Evolución Clonal/genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Biomarcadores de Tumor , Metilación de ADN/efectos de los fármacos , Decitabina/farmacología , Decitabina/uso terapéutico , Heterogeneidad Genética , Estudio de Asociación del Genoma Completo , Humanos , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/mortalidad , Modelos Biológicos , Polimorfismo de Nucleótido Simple , Secuenciación del ExomaRESUMEN
Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.