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1.
Ann Hematol ; 99(5): 991-1006, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32253454

RESUMO

Separase, a cysteine endopeptidase, is a key player in mitotic sister chromatid separation, replication fork dynamics, and DNA repair. Aberrant expression and/or altered separase proteolytic activity are associated with aneuploidy, tumorigenesis, and disease progression. Since genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML), we have comparatively examined separase proteolytic activity in TKI-treated chronic phase CML. Separase proteolytic activity was analyzed on single cell level in 88 clinical samples and in 14 healthy controls by a flow cytometric assay. In parallel, BCR-ABL1 gene expression and replication fork velocity were measured by qRT-PCR and DNA fiber assays, respectively. The separase activity distribution (SAD) value indicating the occurrence of MNCs with elevated separase proteolytic activity within samples was found to positively correlate with BCR-ABL1 gene expression levels and loss of MMR (relapse) throughout routine BCR-ABL1 monitoring. Analyses of CD34+ cells and MNCs fractionized by flow cytometric cell sorting according to their separase activity levels (H- and L-fractions) revealed that CD34+ cells with elevated separase activity levels (H-fractions) displayed enhanced proliferation/viability when compared with cells with regular (L-fraction) separase activity (mean 3.3-fold, p = 0.0011). BCR-ABL1 gene expression positivity prevailed in MNC H-fractions over L-fractions (42% vs. 8%, respectively). Moreover, expanding CD34+ cells of H-fractions showed decreased replication fork velocity compared with cells of L-fractions (p < 0.0001). Our data suggests an association between high separase activity, residual BCR-ABL1 gene expression, and enhanced proliferative capacity in hematopoietic cells within the leukemic niche of TKI-treated chronic phase CML.


Assuntos
Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/administração & dosagem , Separase/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade
2.
Life Sci ; 248: 117467, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105706

RESUMO

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.


Assuntos
DNA de Neoplasias/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucócitos/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Adulto , Alelos , Animais , Grupo com Ancestrais do Continente Asiático , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/biossíntese , Feminino , Xenoenxertos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/etnologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Polimorfismo Genético , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
4.
Lancet Haematol ; 7(3): e218-e225, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978329

RESUMO

BACKGROUND: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. METHODS: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). FINDINGS: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. INTERPRETATION: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. FUNDING: Epidemiological and Clinical Research Information Network.


Assuntos
Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Suspensão de Tratamento
5.
Life Sci ; 243: 117255, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923418

RESUMO

BACKGROUND: The occurrence in drug resistance of chronic myeloid leukemia (CML) was accompanied by autophagy activation. Abnormal circular RNAs (circRNAs) participated in this progression. This study attempted to investigate the potential role of circ_0009910 in imatinib resistance of CML cells. METHODS: The expression of circ_0009910 and miR-34a-5p was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The characterization of circ_0009910 was investigated using oligo (dT)18 primers, Actinomycin D and RNase R. Cell viability (IC50 value) and apoptosis were assessed by Cell Counting Kit-8 (CCK8) assay and flow cytometry assay, respectively. The relative protein expression was quantified by western blot. The relationship among miR-34a-5p, circ_0009910 and ULK1 was predicted by online bioinformatics tool, and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP). RESULTS: The expression of circ_0009910 was up-regulated in the serum of imatinib-resistance CML patients and K562/R cells, and associated with unfavorable clinicopathologic features. Circ_0009910 in K562 and K562/R cells was mainly localized in the cytoplasm. Circ_0009910 knockdown inhibited cell proliferation and autophagy, but induced apoptosis in K562/R cells. Circ_0009910 targeted miR-34a-5p to regulate ULK1. MiR-34a-5p depression rescued the effects of circ_0009910 knockdown on apoptosis and autophagy in K562/R cells. CONCLUSION: Circ_0009910 accelerated imatinib-resistance in CML cells by modulating ULK1-induced autophagy via targeting miR-34a-5p, providing a potential target in imatinib resistance of CML.


Assuntos
Antineoplásicos/uso terapêutico , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/fisiologia , Autofagia/fisiologia , Mesilato de Imatinib/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , MicroRNAs/genética , Resistencia a Medicamentos Antineoplásicos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
6.
Neoplasma ; 67(1): 171-177, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31307197

RESUMO

Increasing evidence demonstrate that circular RNAs (circRNAs) play critical role in regulation of gene expression, which participate in the pathogenesis of cancer, including chronic myeloid leukemia (CML). In this study, we aimed to investigate the expression profiling of circHIPK3 in CML. We found that circHIPK3 was significantly upregulated in peripheral blood mononuclear cells (PBMC) and serum samples from CML compared with healthy controls. High circHIPK3 expression predicted a poor outcome of CML patients. Further loss-function experiments suggested the oncogenic role of circHIPK3 in CML. Our findings provide insights on the role of circHIPK3 in the development and treatment of CML.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Prognóstico , /sangue , Biomarcadores Tumorais/sangue , Progressão da Doença , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos Mononucleares/metabolismo
7.
Eur J Med Chem ; 185: 111748, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648125

RESUMO

Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPARγ agonists on the ability to circumvent resistance, the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1'-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment. Especially the derivatives 18a-f, which did not activate PPARγ to more than 40% at 10 µM, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Telmisartan/farmacologia , Animais , Antineoplásicos/química , Células COS , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Mesilato de Imatinib/química , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Estrutura Molecular , PPAR gama/agonistas , Relação Estrutura-Atividade , Telmisartan/análogos & derivados , Telmisartan/química
8.
Cell Mol Biol Lett ; 24: 66, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31844417

RESUMO

Background: MicroRNAs (miRNAs) function as post-transcriptional gene expression regulators. Some miRNAs, including the recently discovered miR-582-3p, have been implicated in leukemogenesis. This study aimed to reveal the biological function of miR-582-3p in acute myeloid leukemia (AML), which is one of the most frequently diagnosed hematological malignancies. Methods: The expression of miR-582-3p was determined using quantitative real-time PCR in blood samples from leukemia patients and in cell lines. Cell proliferation and cell cycle distribution were analyzed using the CCK-8, colony formation and flow cytometry assays. The target gene of miR-582-3p was verified using a dual-luciferase reporter assay. The G2/M phase arrest-related molecule contents were measured using western blotting analysis. Results: We found miR-582-3p was significantly downregulated in the blood samples from leukemia patients and in the cell lines. MiR-582-3p overexpression significantly impaired cell proliferation and induced G2/M cell cycle arrest in THP-1 cells. Furthermore, cyclin B2 (CCNB2) was confirmed as a target gene of miR-582-3p and found to be negatively regulated by miR-582-3p overexpression. More importantly, CCNB2 knockdown showed suppressive effects on cell proliferation and cell cycle progression similar to those caused by miR-582-3p overexpression. The inhibitory effects of miR-582-3p overexpression on cell proliferation and cell cycle progression were abrogated by CCNB2 transfection. Conclusion: These findings indicate new functions and mechanisms for miR-582-3p in AML development. Further study could clarify if miR-582-3p and CCNB2 are potential therapeutic targets for the treatment of AML.


Assuntos
Ciclina B2/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional/métodos , Ciclina B2/antagonistas & inibidores , Ciclina B2/metabolismo , Feminino , Genes Reporter , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Luciferases/genética , Luciferases/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Células THP-1
9.
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
10.
Zhonghua Nei Ke Za Zhi ; 58(11): 803-807, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665854

RESUMO

Objective: To investigate the influence of additional clonal chromosome abnormalities in Ph negative cells (CCA/Ph(-)) on the efficacy of chronic myeloid leukemia (CML) after tyrosine kinase inhibitors (TKI) treatment. Methods: The clinical data of 28 CML patients with CCA/Ph(-) treated in Henan Cancer Hospital from July 2014 to December 2017 were analyzed retrospectively. The univariate analysis was carried out by Kaplan-Meier method. Multivariate analysis was done by Cox proportional risk model. Results: A total of 28 CCA/Ph(-)patients were recruited including 17 males and 11 females with median age of 42.5 years old. The most common CCA/Ph(-)were trisomy 8 (60.7%), monosomy 7 (14.3%). 64.3% CCA/Ph(-)were transient and 35.7% recurrent (more than 2 times). Cytopenia in two or three lineages of peripheral blood was seen in 42.9% patients. As to the efficacy, 89.3% patients achieved major cytogenetic response (MCyR), 25% with major molecular response (MMR). The median follow-up time was 26.5 months. Treatment failure (TF) of TKI occurred in 32.1% patients with median duration of response 8 (1-41) months. Univariate analysis showed that TF rate was significantly correlated with the frequency of CCA/Ph(-)and cytopenia (all P<0.05). The MMR rate was also significantly correlated with cytopenia (P<0.05). Cytopenia of two lineages or pancytopenia was an independent risk factor related to MMR rate (RR=3.868, 95%CI 1.216-12.298, P=0.022) . Conclusions: Cytopenia in CCA/Ph(-)appears to be an independent risk factor of MMR in CML patients with TKI treatment. The recurrent CCA/Ph(-)may link to higher treatment failure rate. Drug withdrawal or alternative strategy should be considered according to response and the ABL kinase mutations.


Assuntos
Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Falha de Tratamento
11.
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
12.
Biochem Soc Trans ; 47(5): 1307-1325, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31551354

RESUMO

Chronic myeloid leukaemia (CML) is a paradigm of precision medicine, being one of the first cancers to be treated with targeted therapy. This has revolutionised CML therapy and patient outcome, with high survival rates. However, this now means an ever-increasing number of patients are living with the disease on life-long tyrosine kinase inhibitor (TKI) therapy, with most patients anticipated to have near normal life expectancy. Unfortunately, in a significant number of patients, TKIs are not curative. This low-level disease persistence suggests that despite a molecularly targeted therapeutic approach, there are BCR-ABL1-independent mechanisms exploited to sustain the survival of a small cell population of leukaemic stem cells (LSCs). In CML, LSCs display many features akin to haemopoietic stem cells, namely quiescence, self-renewal and the ability to produce mature progeny, this all occurs through intrinsic and extrinsic signals within the specialised microenvironment of the bone marrow (BM) niche. One important avenue of investigation in CML is how the disease highjacks the BM, thereby remodelling this microenvironment to create a niche, which enables LSC persistence and resistance to TKI treatment. In this review, we explore how changes in growth factor levels, in particular, the bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines, impact on cell behaviour, extracellular matrix deposition and bone remodelling in CML. We also discuss the challenges in targeting LSCs and the potential of dual targeting using combination therapies against BMP receptors and BCR-ABL1.


Assuntos
Medula Óssea/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Microambiente Tumoral , Medula Óssea/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
13.
Mol Med Rep ; 20(4): 3597-3608, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485618

RESUMO

Clofarabine (2­chloro­2'­fluoro­2'­deoxyarabinosyladenine, CIF), a second­generation 2'­deoxyadenosine analog, possesses a variety of anti­cancer activities, including the capacity to modulate DNA methylation marks. Bioactive nutrients, including resveratrol (RSV) and all­trans retinoic acid (ATRA) have been indicated to regulate epigenetic machinery in malignant cells. The purpose of the current study was to evaluate whether the tested phytochemicals, RSV or ATRA, can improve the therapeutic epigenetic effects of CIF in chronic myeloid leukemia (CML) cells. The present study investigates, to the best of our knowledge, for the first time, the influence of CIF in combination with RSV or ATRA on the expression of relevant modifiers of DNA methylation machinery, including DNA Methyltransferase 1 (DNMT1) and Cyclin dependent kinase inhibitor 1A (CDKN1A) in CML cells. Subsequently, the combinatorial effects on promoter methylation and transcript levels of methylation­silenced tumor suppressor genes (TSGs), including phosphatase and tensin homologue (PTEN) and retinoic acid receptor beta (RARB), were estimated using MSRA and qPCR, respectively. The tested TSGs were chosen according to bioinformatical analysis of publicly available clinical data of human DNA methylation and gene expression arrays in leukemia patients. The K562 cell line was used as an experimental CML in vitro model. Following a period of 72 h exposure of K562 cells, the tested combinations led to significant cell growth inhibition and induction of caspase­3­dependent apoptosis. These observations were accompanied by DNMT1 downregulation and CDKN1A upregulation, with a concomitant enhanced decrease in DNMT1 protein level, especially after ATRA treatment with CIF. Concurrent methylation­mediated RARB and PTEN reactivation was detected. The results of the current study demonstrated that CIF that was used in combination with the tested phytochemicals, RSV or ATRA, exhibited a greater ability to remodel DNA methylation marks and promote cell death in CML cells. These results may support the application of CIF combinations with natural bioactive agents in anti­leukemic epigenetic therapy.


Assuntos
Antineoplásicos/farmacologia , Clofarabina/farmacologia , Metilação de DNA/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Resveratrol/farmacologia , Tretinoína/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
14.
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
15.
Med Sci Monit ; 25: 6812-6819, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506418

RESUMO

BACKGROUND Human chronic myelogenous leukemia (CML) is a hematopoietic stem cell disorder with high malignant and invasive activity. lncRNA SNHG5 has been reported to be upregulated in CML. However, whether it affects the proliferation, differentiation, and apoptosis in CML cells is still unknown. This study investigated the role of SNHG5 in CML and revealed the potential mechanism. MATERIAL AND METHODS K562 cells were transfected with shRNA, and the expression level of SNHG5 was assessd by quantitative RT-PCR. The proliferation ability was determined by CCK-8 assay. Western blot analysis was performed to detect protein expressions related to cell proliferation, differentiation, and apoptosis. Cell apoptosis rate was analyzed by flow cytometry. The DNA methylation level was determined by methylation-specific PCR (MSP). RESULTS Our results show that inhibition of SNHG5 induced by RNA interference significantly inhibits K562 cells proliferation and induces cell differentiation with the increased expression of CD42b, CD11b, CD14, GATA-1, and ß-globin. Flow cytometry analysis indicated that inhibition of SNHG5 significantly induced cell apoptosis with decreased expression of Bcl-2 and increased expression of Bax and cleaved capase-3. Additionally, Western blot and MSP analyses confirmed that inhibition of SNHG5 increased the expression of DR4 gene through suppressing its methylation. CONCLUSIONS Inhibition of SNHG5 suppressed K562 cell proliferation through inducing the differentiation and apoptosis by inhibiting methylation of DR4. Therefore, downregulated SNHG5 could play a key role in CML progression, and might provide a new strategy for the treatment of CML.


Assuntos
Apoptose/genética , Diferenciação Celular/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , RNA Longo não Codificante/metabolismo , Caspase 3/metabolismo , Proliferação de Células/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Células K562 , RNA Longo não Codificante/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína X Associada a bcl-2/metabolismo
16.
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
17.
Indian J Med Res ; 149(5): 600-609, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31417027

RESUMO

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Tiazóis/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Análise Custo-Benefício , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Pediatria/tendências , Pirimidinas/uso terapêutico
18.
Int J Nanomedicine ; 14: 5581-5594, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413564

RESUMO

Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder due to the existence of BCR-ABL fusion protein that allows the cells to keep proliferating uncontrollably. Although tyrosine kinase inhibitors can inhibit the activity of BCR-ABL fusion protein to trigger the cells apoptosis, drug resistance or intolerance exists in part of CML patients. Arsenic sulfide in its raw form (r-As4S4) can be orally administrated and certain therapeutic effects have been found out in the treatment of hematologic malignancies through inducing cell apoptosis. Methods: In this work, a water-dissolvable arsenic sulfide nanoformualtion (ee-As4S4) composed of As4S4 particulates with 470 nm in diameter and encapsulated by a kind of hydrophilic polymer was fabricated and applied to the CML cell line K562, K562/AO2 and primary cells from the bone marrow of CML patients. Results: Results showed that instead of inhibiting the activity of BCR-ABL, ee-As4S4 induced direct degradation of BCR-ABL in K562 cells within 6 hr incubation, followed by the occurrence of erythroid differentiation in K562 after 72 hr incubation, evidenced by the significantly upregulated CD235a and benzidine staining, which was not detectable with r-As4S4. The ee-As4S4-induced erythroid differentiation was also observed in K562/AO2 cells and bone marrow mononuclear cells of CML patients. Mechanistic studies indicated that ee-As4S4 induced autophagy by downregulating the level of intracellular ROS and hypoxia-inducible factor-1α significantly, which led to the subsequent degradation of BCR-ABL. When the concentration was increased, ee-As4S4 induced much more significant apoptosis and cell cycle arrest than r-As4S4, and the cytotoxicity of the former was about 178 times of the latter. Conclusion: ee-As4S4 was capable of inducing significant erythroid differentiation of CML cells by inducing the direct degradation of BCR-ABL; the new effect could improve hematopoietic function of CML patients as well as inhibit the leukemic cell proliferation.


Assuntos
Arsenicais/farmacologia , Diferenciação Celular/efeitos dos fármacos , Composição de Medicamentos , Células Eritroides/citologia , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nanopartículas/química , Proteólise/efeitos dos fármacos , Sulfetos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Eritroides/efeitos dos fármacos , Células Eritroides/ultraestrutura , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Anticancer Res ; 39(8): 4333-4335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366526

RESUMO

Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.


Assuntos
Doença de Hodgkin/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Segunda Neoplasia Primária/genética , Proteínas de Fusão bcr-abl/genética , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/patologia , Proteínas Proto-Oncogênicas c-bcr/genética
20.
Chem Biodivers ; 16(10): e1900443, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468670

RESUMO

Chronic myelogenous leukemia (CML) is a disease of the blood stem cells that features the oncoprotein Bcr-Abl. Tyrosine kinase inhibitors (TKIs) are used to treat CML patients, but these have limited efficacy due to the emergence of resistance via genetic mutation. Kamebakaurin is an ent-kaurane diterpenoid that has been isolated from Rabdosia excisa (Maxim.) H.Hara. Herein, we investigate the potential of kamebakaurin as a chemotherapy reagent for the treatment of CML. We conducted in vitro and in vivo biological experiments and found that kamebakaurin potently inhibits cell proliferation, mainly by enhancing cell apoptosis and down-regulating Bcr-Abl protein levels. In addition, kamebakaurin was found to inhibit tumor growth and has no side effects on five internal organs for in vivo experiment. These results suggest that kamebakaurin is a potential anticancer agent and is a key compound for further investigations.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Isodon/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
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