RESUMO
The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Cromossomos Humanos Par 14/genética , Hematopoiese Clonal , Duplicação Gênica , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Repressoras/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Suscetibilidade a Doenças , Feminino , Seguimentos , Células Germinativas , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , RNA Helicases DEAD-box/genética , Infecções por HTLV-I/genética , Leucemia-Linfoma de Células T do Adulto/genética , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas dos Retroviridae/genética , Ribonuclease III/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/virologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/virologia , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas dos Retroviridae/metabolismo , Ribonuclease III/metabolismo , Ácido Valproico/administração & dosagemRESUMO
PURPOSE: To describe the retinal manifestations in adult T-cell leukemia (ATL) related to an infection by the human T-cell lymphotropic virus type-1 (HTLV-1). METHODS: Retrospective case series of patients with ATL with retinal findings. RESULTS: A total of 175 patients were diagnosed with ATL in Martinique between 1983 and 2013. Three of them showed intraocular findings related to ATL. They were bilateral deep retinal infiltrates associated with intermediate uveitis. In two cases, the ATL diagnosis was known. In the third, fluorescein angiography was remarkable for deep retinal infiltrates although fundus examination was unremarkable. The ATL cells were found in the blood of this patient. Despite chemotherapy, infiltrates progressed from the retinal periphery to the posterior pole in two patients, thus reducing visual acuity to light perception. They were associated with vasculitis. CONCLUSION: Retinal involvement in ATL is very rare. It can occur at any point during the natural course of the disease. Human T-cell lymphotropic virus type-1 carriers should benefit from a regular ophthalmic examination, and a fluorescein angiography must be performed in all patients with human T-cell lymphotropic virus type-1 with vitreous cells. The presence of deep retinal infiltrates must raise suspicion for ATL in a patient with human T-cell lymphotropic virus type-1.
Assuntos
Infecções Oculares Virais/virologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Leucemia-Linfoma de Células T do Adulto/virologia , Neoplasias da Retina/virologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/tratamento farmacológico , Evolução Fatal , Feminino , Angiofluoresceinografia , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/tratamento farmacológico , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.