RESUMEN
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.
Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Cromosomas Humanos Par 14/genética , Hematopoyesis Clonal , Duplicación de Gen , Leucemia Mieloide Aguda/patología , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/patología , Proteínas Represoras/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN , Susceptibilidad a Enfermedades , Femenino , Estudios de Seguimiento , Células Germinativas , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenAsunto(s)
Proteínas Relacionadas con la Autofagia/genética , Células Germinativas , Leucemia Mieloide Aguda , Proteínas Represoras/genética , Proteínas de Transporte Vesicular/genética , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Prevalencia , Indias OccidentalesRESUMEN
We report here two cases of thrombocytopenic purpura at onset of Zika virus infection. A 26-year-old woman and a 21-year-old man had thrombocytopenia above 5×10(9) platelets/L. Hemorrhagic symptoms were mucosal and subcutaneous bleeding and gross hematuria and they reported episode of conjunctivitis. In both cases blood and bone marrow analysis suggested thrombocytopenic purpura, blood PCR tests for Dengue (DENV), Chikungunya (CHIKV) and Zika virus (ZIKV) were negative. In both cases urinary PCR for ZIKV was positive, Prednisolone yielded early remission. Only three similar cases have been reported so far. In the Caribbean, DENV is also epidemic and responsible for severe thrombocytopenia. Coinfections can occur. Our report underlines the need to include a ZIKV assay in the diagnostic work-up of thrombocytopenic purpura in epidemic areas.
Asunto(s)
Púrpura Trombocitopénica , Infección por el Virus Zika , Virus Zika , Adulto , Femenino , Humanos , Masculino , Púrpura Trombocitopénica/complicaciones , Púrpura Trombocitopénica/diagnóstico , Adulto Joven , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/diagnósticoRESUMEN
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.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , ARN Helicasas DEAD-box/genética , Infecciones por HTLV-I/genética , Leucemia-Linfoma de Células T del Adulto/genética , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas de los Retroviridae/genética , Ribonucleasa III/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Línea Celular Tumoral , ARN Helicasas DEAD-box/metabolismo , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Infecciones por HTLV-I/tratamiento farmacológico , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/virología , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/virología , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas de los Retroviridae/metabolismo , Ribonucleasa III/metabolismo , Ácido Valproico/administración & dosificaciónRESUMEN
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.
Asunto(s)
Infecciones Virales del Ojo/virología , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia-Linfoma de Células T del Adulto/virología , Neoplasias de la Retina/virología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones Virales del Ojo/diagnóstico , Infecciones Virales del Ojo/tratamiento farmacológico , Resultado Fatal , Femenino , Angiografía con Fluoresceína , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/tratamiento farmacológico , Humanos , Interferón-alfa/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/tratamiento farmacológico , Estudios Retrospectivos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Zidovudina/uso terapéuticoRESUMEN
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.
