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1.
Anticancer Res ; 40(5): 2457-2465, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366389

RESUMO

The introduction of tyrosine kinase inhibitors (TKIs) directed against the catalytic activity of the ABL tyrosine kinase has considerably improved the outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease. Indeed, these individuals currently show a life-expectancy comparable to those of healthy subjects. Currently, five TKIs (imatinib, dasatinib, nilotinib, bosutinib and ponatinib) are approved for the treatment of CML and can be used as first, second or further lines of treatment according to disease risk scores, patient comorbidities and the presence of known TKI resistance mechanisms. In fact, 15-20% of all CML patients fail to achieve optimal responses according to the current definitions of the European Leukemia Network and will require sequential TKI treatment to avoid disease progression. In this review, we present the state of art in several crucial areas of CML management by briefly: i) depicting the domain structure of the BCR-ABL1 oncoprotein; ii) describing pivotal data concerning TKI efficacy; iii) illustrating the diverse molecular mechanisms causing TKI resistance; and iv) summarizing new ABL1-directed therapeutic approaches that are presently under investigation.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-abl/genética , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(9): e19256, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118733

RESUMO

INTRODUCTION: We report here the case of a patient with chronic myeloid leukemia (CML) in the chronic phase who was diagnosed 1 year after receiving a diagnosis of autoimmune hemolytic anemia (AIHA). The objective was to assess if the CML patient progressed from AIHA and explore the underlying factors of the poor outcome after the achievement of molecular complete remission (MCR). PATIENT CONCERNS: A patient with AIHA underwent splenectomy because of poor response to immune inhibitors. The spleen biopsy showed reactive hyperplasia. DIAGNOSIS: The patient was diagnosed with CML because of over-expression of the BCR-ABL (P210) gene in the bone marrow (BM), 1 year after receiving the diagnosis of AIHA. INTERVENTIONS: The splenectomy was performed as the patient was unresponsive to the standard treatments consisting of immunoglobulin and dexamethasone. The removed spleen was sent for pathological examination. After she was diagnosed with CML, she received imatinib treatment. OUTCOMES: The spleen biopsy confirmed the translocation of 22q11/9q34. No BCR-ABL kinase domain mutation was detected and there was no expression of the WT1 or EVI1 genes. After splenectomy, the number of peripheral white blood cells was consistently higher than normal during the total therapy time for CML even though she showed MCR. Two years after CML was diagnosed, the patient died from severe infection. The BM gene array analysis displayed 3 types of chromosomal abnormalities: gain (14q32.33), uniparental disomy (UPD) Xp11.22-p11.1), and UPD Xp11.1-q13.1. LESSONS: AIHA may be a clinical phase of CML progression in this patient. Both splenectomy and prolonged oral tyrosine kinase inhibitors may have contributed to the high risk of infection and her subsequent death. In addition, the gain of chromosome 14q32.33 may be related to her poor outcome.


Assuntos
Anemia Hemolítica Autoimune , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Adolescente , Evolução Fatal , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Esplenectomia
3.
PLoS One ; 15(2): e0229104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106243

RESUMO

Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34-/CD38-, BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and ß-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Células 3T3 , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Perfilação da Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Camundongos , Mutação/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Domínios Proteicos/genética , Inibidores de Proteínas Quinases/uso terapêutico
4.
Ann Hematol ; 99(4): 829-834, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32107574

RESUMO

A single-center retrospective was performed with consecutive de novo BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients who received TKI-containing therapy between January 2010 and December 2018 to review the incidence, treatment, and outcome of the T315I mutation. A total of 38 (18%) patients harbored the T315I mutation in this period. According to the type of salvage therapy, patients were divided into subgroups of hematopoietic stem cell transplantation (HSCT) recipients (n = 9) and HSCT nonrecipients (n = 29). In the latter subgroup, there were 7 patients who newly acquired the T315I mutation after HSCT, and the median time was 10.8 months. In addition to these 7 cases, 5 out of 22 patients were managed with chimeric antigen receptor (CAR) T cells and ponatinib. There were 4 patients in the HSCT recipient subgroup who were treated with CAR-T cells or ponatinib before HSCT. The complete molecular remission (CMR) and recurrence rate of HSCT recipients were both 67%, and the median recurrence time was 3.6 months. A better overall survival (OS) was observed in the HSCT recipient subgroup than in the HSCT nonrecipient subgroup (median of 12.3 months vs 3.3 months, respectively; p = 0.004). Compared with patients who were not bridging to HSCT, the patients who were treated with CAR-T cells and/or ponatinib and bridged to HSCT tended to have a better OS (median of 3.3 months vs 13.3, respectively; p = 0.09). In conclusion, the outcomes in ALL patients with the T315I BCR-ABL1 mutation were poor. A better OS can be achieved through ponatinib, CAR-T cells, and bridging to HSCT, but it also has a higher risk of recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Genes abl , Imidazóis/uso terapêutico , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Adolescente , Adulto , Substituição de Aminoácidos , Terapia Combinada , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Indução de Remissão , Risco , Terapia de Salvação , Adulto Jovem
5.
Medicine (Baltimore) ; 99(5): e18811, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000382

RESUMO

RATIONALE: Concurrent calreticulin (CALR) mutation and BCR-ABL1 fusion are extremely rare in chronic myelogenous leukemia; to date, only 12 cases have been reported. PATIENT CONCERNS: A 57-year-old male who had an 11-year history of essential thrombocytosis presented to our hospital with leukocytosis and marked splenomegaly for 3 months. DIAGNOSES: Chronic myelogenous leukemia with myeloid fibrosis arising on the background of essential thrombocytosis harboring both BCR-ABL1 fusion and type-1 like CALR mutation. INTERVENTIONS: Imatinib was started at 300 mg daily and increased to 400 mg daily after 3 months; interferon was added after 12 months. OUTCOMES: Partial cytogenetic response was achieved after 3 months of imatinib therapy and complete cytogenetic response was achieved after 1 year of treatment. However, CALR mutation was still present with a stable mutational allele burden. LESSONS: In this case report and review of additional 12 cases with simultaneous presence of CALR-mutation and BCR-ABL1 fusion, we highlighted the importance of integrating clinical, morphological, and molecular genetic data for classifying atypical myeloid neoplasms.


Assuntos
Calreticulina/genética , Proteínas de Fusão bcr-abl/genética , Genes abl , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Trombocitemia Essencial/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/antagonistas & inibidores , Trombocitemia Essencial/complicações
7.
Bull Cancer ; 107(1): 113-128, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31353136

RESUMO

In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.


Assuntos
Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação de Sentido Incorreto , Mutação Puntual , Antineoplásicos/uso terapêutico , Domínio Catalítico , Tomada de Decisão Clínica , DNA de Neoplasias/análise , Resistencia a Medicamentos Antineoplásicos/genética , Substituição de Medicamentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Biologia Molecular , Domínios Proteicos , Inibidores de Proteínas Quinases/uso terapêutico , Papel (figurativo)
8.
Ann Lab Med ; 40(1): 72-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432643

RESUMO

Accurate detection of BCR-ABL fusion transcripts at and below molecular response (MR) 4 (0.01% International Scale [IS]) is required for disease monitoring in patients with chronic myeloid leukemia (CML). We evaluated the analytical performance of the QXDx BCR-ABL %IS (Bio-Rad, Hercules, CA, USA) droplet digital PCR (ddPCR) assay, which is the first commercially available ddPCR-based in vitro diagnostics product. In precision analysis, the %CV was 9.3% and 3.0%, with mean values of 0.031% IS and 9.4% IS, respectively. The assay was linear in the first order, ranging from 0.032% IS to 20% IS. The manufacturer-claimed limit of blank, limit of detection, and limit of quantification were verified successfully. There was a very strong correlation between the results of the QXDx BCR-ABL %IS ddPCR assay and the ipsogen BCR-ABL1 Mbcr IS-MMR (Qiagen, Hilden, Germany) real-time quantitative PCR assay (r=0.996). In conclusion, the QXDx BCR-ABL %IS ddPCR assay can provide reliable results for CML patients.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Reação em Cadeia da Polimerase/métodos , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Humanos , Limite de Detecção , Kit de Reagentes para Diagnóstico
9.
Zhonghua Nei Ke Za Zhi ; 59(1): 35-39, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887834

RESUMO

Objective: To explore the relationship between driver gene mutation (JAK2, MPL and CALR) and disease type in BCR-ABL negative myeloproliferative neoplasms (MPNs) including primary myeloid fibrosis (PMF), essential thrombocytosis (ET) and polycythemia vera (PV). Methods: A total of 32 MPN related genes were detected by high-throughput sequencing in 156 MPN patients. The relationships between disease type and patients' general performance, the characteristics of driver gene mutations, concomitant gene mutations were analyzed. Results: In the population with JAK2 V617F positive mutation, the proportion of patients over 60 years old in PMF was higher than that with ET or PV. By high-throughput sequencing, 22 concomitant gene mutations were detected in 46 patients with JAK2, MPL or CALR mutations, including 4 (8.3%) in PV, 20 (29.4%) in ET, and 22 (55.0%) in PMF. DNMT3A mutation was detected only in patients with PV, while splicing factor related genes including SF3B1, SRSF2 and U2AF1 were only accompanied by PMF. According to the variation allele frequency (VAF) value of JAK2 V617F mutation, the VAF value associated with PV was the highest (68.15%), followed by PMF (37.7%) and ET (23%). However, there were significant differences in the incidence of JAK2 V617F homozygous among 3 different diseases. In patients with JAK2 mutation, the proportion of other gene mutations in PV and ET was significantly lower than that in PMF. Conclusions: Under the condition of common driver gene mutations (JAK2, MPL and CALR), patients' age, VAF value and homozygous state, concomitant gene mutations are closely related to different disease type. These correlations help to improve clinical understanding of disease characteristics and risk assessment.


Assuntos
Calreticulina/genética , Proteínas de Fusão bcr-abl/genética , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Receptores de Trombopoetina/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Calreticulina/metabolismo , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/metabolismo , Policitemia Vera/genética , Mielofibrose Primária/genética , Receptores de Trombopoetina/metabolismo , Trombocitemia Essencial/genética
10.
Neoplasma ; 67(1): 158-163, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31884803

RESUMO

The BCR/ABL preleukemic fusion gene (PFG) is one of the most frequent fusion genes in acute lymphoblastic leukemia (ALL) and was also detected in hematopoietic cells from umbilical cord blood (UCB) of healthy newborns. Since hematopoietic stem/progenitor cells (HSPC) are considered to be a critical cellular target for origination of leukemia, we have studied the presence of BCR/ABL PFG in expanded subpopulations of HSPC and differentiated cells from UCB of those healthy newborns, who have previously been tested positive for BCR/ABL by screening of their UCB mononuclear cells using RT-qPCR and FISH methods. We isolated cells from human UCB samples positive for BCR/ABL and negative controls. The isolated cells were sorted into 5 hematopoietic and progenitor cell subpopulations. We analyzed BCR/ABL in sorted and expanded subpopulations of UCB using FISH and RT-qPCR. We found that the number of BCR/ABL positive cells was similar in each studied subpopulation and the same as in differentiated lymphocytes. Our data showed that there is no specific subpopulation of hematopoietic and progenitor stem cells with an increased leukemogenic potential due to the presence of higher copies of BCR/ABL.


Assuntos
Sangue Fetal/citologia , Proteínas de Fusão bcr-abl/genética , Células-Tronco Hematopoéticas/citologia , Humanos , Recém-Nascido
12.
Anticancer Res ; 39(12): 6965-6971, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810968

RESUMO

BACKGROUND/AIM: The Philadelphia chromosome is the most frequent cytogenetic abnormality in chronic myelogenous (CML). More than 95% of CML patients are diagnosed with the e13a2 or e14a2 BCR-ABL1 fusion transcripts while, in about 1% of these individuals, the break generates the e1a2 rearrangement. Furthermore, about 5% of CML patients are diagnosed with rare BCR-ABL1 fusion transcripts, such as e19a2, e8a2, e13a3, e14a3, e1a3 and e6a2. However, there is limited evidence concerning the clinical and prognostic implications of these infrequent oncogenic variants for CML patients receiving tyrosine kinase inhibitors (TKIs). CASE REPORT: We describe a novel atypical e12a2 insertion/deletion (Ins/Del) BCR-ABL1 fusion identified in a CML 59-year-old man diagnosed with a common e13a2 BCR-ABL1 isoform. The use of primers recognizing more distant exons from the common BCR-ABL1 breakpoint region correctly identified and monitored in time the atypical e12a2 Ins/Del BCR-ABL1 fusion. CONCLUSION: Treatment with second- (nilotinib) and third-generation (ponatinib) TKIs was effective in suppressing leukemic clones exhibiting the atypical e12a2 Ins/Del BCR-ABL1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Humanos , Mutação INDEL , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento
13.
N Engl J Med ; 381(24): 2315-2326, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31826340

RESUMO

BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacocinética
14.
Int J Mol Sci ; 21(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861691

RESUMO

Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These 'hits' do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2,associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This 'hardwiring' of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem da Célula , Proteínas de Fusão bcr-abl/genética , Humanos , Proteínas com Domínio LIM/genética , Leucemia/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/genética
15.
Clin Adv Hematol Oncol ; 17(12): 686-696, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31851157

RESUMO

Tyrosine kinase inhibitors (TKIs) represent a major breakthrough in the treatment of chronic myeloid leukemia (CML). Thanks to these agents, CML has been transformed from a disease with limited treatment options and a dismal prognosis into a more indolent disease with survival comparable to that of the general population. The need for ongoing TKI therapy remains controversial for several reasons, including cost and toxicity. Studies in CML patients with a sustained deep molecular response have demonstrated that stopping TKI therapy is feasible and safe. Given the heterogeneity of results reported in clinical trials, practice guidelines for optimal patient selection and proper monitoring after discontinuation of TKIs are proposed outside of clinical trials. Current data available show that 40% to 60% of patients who stop therapy relapse; molecular relapses typically occur within 6 months, but nearly all relapsing patients regain response upon reinitiation of the TKI. Several factors that predict for relapse have been investigated. Duration of prior TKI therapy, achievement of deep molecular response, depth of molecular response, prior interferon treatment, and Sokal risk score have been shown to be potential predictors for relapse. Leukemia stem cells that are resistant to TKIs, and that persist despite undetectable BCR/ABL1 transcript levels, likely are responsible for disease relapse after discontinuation. Efforts geared toward better identification of low levels of BCR/ABL1 transcript using new techniques such as digital polymerase chain reaction, along with eradicating CML clones using combination therapies with agents such as pegylated interferon or venetoclax with TKIs, will hopefully lead to a functional cure of this disease.


Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Recidiva
16.
BMC Cancer ; 19(1): 935, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594548

RESUMO

BACKGROUND: Although extensive use of tyrosine kinase inhibitors has resulted in high and durable response rate and prolonged survival time in patients with BCR-ABL1 positive chronic myeloid leukemia (CML) and acute leukemia, relapse and drug resistance still remain big challenges for clinicians. Monitoring the expression of BCR-ABL1 fusion gene and identifying ABL kinase mutations are effective means to predict disease relapse and resistance. However, the prognostic impact of BCR-ABL1 signal patterns detected by fluorescence in situ hybridization (FISH) remains largely unaddressed. METHODS: BCR-ABL1 signal patterns were analyzed using FISH in 243 CML-chronic phase (CML-CP), 17 CML-blast phase (CML-BP) and 52 BCR-ABL1 positive acute lymphoblastic leukemia (ALL) patients. RESULTS: The patterns of BCR-ABL1 signals presented complexity and diversity. A total of 12 BCR-ABL1 signals were observed in this cohort, including 1R1G2F, 1R1G1F, 2R1G1F, 1R2G1F, 2R2G1F, 1R2G2F, 1R1G3F, 1G3F, 2G3F, 1G4F, 1R1G4F and 1R4F. Complex BCR-ABL1 signal patterns (≥ two types of signal patterns) were observed in 52.9% (n = 9) of the CML-BP patients, followed by 30.8% (n = 16) of the ALL patients and only 2.1% (n = 5) of the CML-CP patients. More importantly, five clonal evolution patterns related to disease progression and relapse were observed, and patients with complex BCR-ABL1 signal patterns had a poorer overall survival (OS) time compared with those with single patterns (5.0 vs.15.0 months, p = 0.006). CONCLUSIONS: Our data showed that complex BCR-ABL1 signal patterns were associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia. Monitoring BCR-ABL1 signal patterns might be an effective means to provide prognostic guidance and treatment choices for these patients.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Evolução Clonal , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
17.
Nat Commun ; 10(1): 4741, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628323

RESUMO

Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.


Assuntos
Quinase 8 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Proteínas de Fusão bcr-abl/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Quinase 8 Dependente de Ciclina/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
18.
Exp Hematol ; 77: 36-40.e2, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31493432

RESUMO

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are the cornerstone of treatment in chronic myeloid leukemia. Although there are now four TKIs approved for use in the front-line setting, acquired TKI resistance via secondary kinase domain mutations remains a problem for patients. K0706 is a novel BCR-ABL1 TKI currently under clinical investigation with structural elements similar to those of ponatinib and dasatinib. In this article, we functionally characterize the anti-leukemic activity of K0706 using cell proliferation assays in conjunction with drug resistance screening. We provide details from molecular modeling to support our in vitro findings and additionally describe our limited clinical experience with this drug in two patients treated on trial. We demonstrate that although K0706 retains efficacy against a large spectrum of clinically relevant mutations, it does not appear to have activity against BCR-ABL1T315I. Early trial experience suggests excellent tolerability, which may positively affect the place of K0706 within the ever-expanding chronic myeloid leukemia treatment paradigm.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos
19.
In Vivo ; 33(5): 1593-1598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471409

RESUMO

BACKGROUND/AIM: As approximately 10% of individuals developing chronic myeloid leukemia (CML) are females aged 20-44 years, a considerable number will consider a planned pregnancy if disease is well controlled by pharmacological treatment. The management of these young patients during pregnancy represents a therapeutic dilemma due to the potential teratogen effects of several tyrosine kinase inhibitors (TKIs) and is a matter of continuous debate. Indeed, despite the existence of several studies, there is currently no consensus on how to manage different pregnancy situations in subjects with CML. PATIENTS AND METHODS: We describe a female patient diagnosed with Ph-positive CML one month after her first delivery who achieved excellent hematological, cytogenetic and molecular responses while on imatinib mesylate (IM) treatment. RESULTS: The excellent responses allowed the patient to suspend TKI treatment in order to plan a second pregnancy. Despite IM discontinuation, stringent molecular monitoring of her BCR-ABL1/ABL1 levels allowed the safe delivery of the child and, while the patient eventually developed a molecular relapse after four years of treatment discontinuation, upon restarting IM she quickly regained a deep molecular response that is still ongoing. CONCLUSION: Our case report demonstrates that, if the pregnancy is properly planned in CML patients, it can result in excellent management of the clinical therapeutic option for the benefit of both mother and child.


Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores , Biópsia , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
20.
Biomed Pharmacother ; 119: 109413, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518872

RESUMO

MicroRNA-mediated posttranscriptional regulation is an important epigenetic regulatory mechanism of gene expression, and its dysregulation is involved in the development and progression of a variety of malignancies, including chronic myeloid leukemia (CML). The BCR-ABL1 fusion gene is not only the initiating factor of CML, but it is also an important driving factor for blastic transformation. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase activity, represented by imatinib, are currently the first-line treatment for CML. However, due to primary resistance or secondary resistance caused by mutations in the BCR-ABL1 kinase domain, TKIs cannot completely prevent the progression of CML; thus, the study of BCR-ABL1 gene expression regulation is of great significance. In this study, bioinformatics analysis and our results showed that miR-96 could directly bind to the 3'UTR region of BCR-ABL1 to regulate fusion protein expression, thereby regulating its downstream signaling pathway activity. We also found that miR-96 was downregulated during the progression from the chronic phase (CML-CP) to the blast crisis (CML-BC). Downregulation of miR-96 could promote the proliferation and participate in the cell differentiation of CML-BC cells. Additionally, we found that the novel histone deacetylase drug chidamide and the DNA methyltransferase inhibitor decitabine could restore the low expression of miR-96 in CML cells, and there were two abnormal hypermethylated sites in the promoter region of miR-96 in CML, suggesting that its low expression might be at least partially regulated by epigenetic mechanisms. In addition, re-expression of miR-96 could increase the sensitivity of CML-BC cells to imatinib. Thus, miR-96 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in CML blastic transformation.


Assuntos
Crise Blástica/genética , Transformação Celular Neoplásica/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética , Oncogenes , Regiões 3' não Traduzidas/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Sequência de Bases , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Crise Blástica/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Decitabina/farmacologia , Decitabina/uso terapêutico , Regulação para Baixo/genética , Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MicroRNAs/metabolismo , Biossíntese de Proteínas
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