RESUMO
Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin-Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas ras/metabolismoRESUMO
Extranodal natural killer/T cell lymphoma, nasal type (ENK/TCL), is an aggressive and rare hematological malignancy. Patients with advanced and relapsed/refractory disease have very poor outcomes. In this study, we retrospectively assessed the efficacy and safety of MEDA regimen (methotrexate, etoposide, dexamethasone and pegaspargase) in the treatment of advanced and relapsed/refractory ENK/TCL patients. Thirteen patients received a total of 55 cycles of MEDA, with a median of four cycles. At the completion of treatment, the overall response rate was 76.9 %, with a complete response rate of 61.5 %. The 1-year overall survival rate was 69.2 %, and 1-year progression-free survival was 61.5 %. Treatment-related toxicity was monitored in all patients. Grade 3/4 neutropenia occurred in 46.2 % of patients. Serious infections happened in two cases (15.4 %). Grade 3/4 thrombocytopenia occurred in 30.8 % of patients, and 23.1 % received platelet transfusion. Grade 3/4 anemia was observed in 23.1 % of patients. Hepatotoxicity and low fibrinogen were common, but mild. These results show that MEDA regimen is very effective with tolerable adverse effects in the treatment of advanced and relapsed/refractory ENK/TCL. Further prospective trials are expected to validate the efficacy of MEDA in an expanded number of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Dexametasona/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/radioterapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Polietilenoglicóis/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an interferon (IFN)-induced molecule with apoptotic activity. We examined gene mutations in the death domains of TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), and in the TRAIL gene promoter in 46 chronic myelogenous leukemia (CML) patients. In 23 of the 46 patients, all the coding regions of TRAIL-R2 were also examined. However, no mutation or loss of heterozygosity was found. Furthermore, no mutation in the death domains of TRAIL-R1 and TRAIL-R2 genes, which causes amino acid change, was found in 18 myelodysplastic syndrome (MDS) patients. Ribonuclease protection assay (RPA) and real-time quantitative polymerase chain reaction using polymorphonuclear neutrophils of five new CML patients showed that the TRAIL mRNA expression was very low before in vitro IFN-alpha stimulation and markedly upregulated after IFN-alpha stimulation. FAS mRNA was also upregulated with IFN-alpha stimulation but the fold induction was far lower than that of TRAIL mRNA. In addition, RPA revealed that the ratio of (TRAIL-R1 plus TRAIL-R2) to TRAIL-R3 was also increased after IFN-alpha stimulation. Taken together, gene mutations of TRAIL-R1, TRAIL-R2 are infrequent in patients with CML and MDS. And so is the TRAIL promoter for CML. These mutations seem unrelated to tumorigenesis, disease progression, and response to IFN-alpha therapy in CML. A markedly high induction of TRAIL mRNA by IFN-alpha may have some relevance to IFN-alpha action in CML patients.
Assuntos
Substituição de Aminoácidos/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Perda de Heterozigosidade/genética , Síndromes Mielodisplásicas/genética , Receptores do Fator de Necrose Tumoral/genética , Proteínas Reguladoras de Apoptose , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Estrutura Terciária de Proteína/genética , RNA Mensageiro/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genéticaRESUMO
We describe a patient with chronic myelogenous leukemia (CML), in whom the DNA breakpoint in the BCR-ABL fusion gene was determined to result in a rare e13a3 (b2a3) transcript. The breakpoint in BCR was intron 13, which was 30 bp downstream from exon 13, and the breakpoint in ABL was intron 2, and was 46 bp downstream from exon a2. This case conforms to the mechanism of DNA breakage occurring within ABL intron 2, but not at 5' to ABL exon a2. With our review of this case and the literature, it seems that CML with the BCR-a3 fusion product is associated with a low proportion of circulating immature cells, mild or lack of splenomegaly, slow progressiveness, rather resistance to IFN-alpha, and good response to imatinib mesylate. This is the first report of BCR-a3-type CML in which the exact DNA breakpoint was identified and located between exons a2 and a3 of the ABL gene.
