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1.
Haematologica ; 99(1): 37-45, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23996481

RESUMEN

Myelofibrosis is a myeloproliferative neoplasm that occurs de novo (primary myelofibrosis) or results from the progression of polycythemia vera or essential thrombocytemia (hereafter designated as secondary myelofibrosis or post-polycythemia vera/ essential thrombocythemia myelofibrosis). To progress in the understanding of myelofibrosis and to find molecular prognostic markers we studied 104 samples of primary and secondary myelofibrosis at chronic (n=68) and acute phases (n=12) from 80 patients, by using array-comparative genomic hybridization and sequencing of 23 genes (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). We found copy number aberrations in 54% of samples, often involving genes with a known or potential role in leukemogenesis. We show that cases carrying a del(20q), del(17) or del(12p) evolve in acute myeloid leukemia (P=0.03). We found that 88% of the cases were mutated, mainly in signaling pathway (JAK2 69%, NF1 6%) and epigenetic genes (ASXL1 26%, TET2 14%, EZH2 8%). Overall survival was poor in patients with more than one mutation (P=0.001) and in patients with JAK2/ASXL1 mutations (P=0.02). Our study highlights the heterogeneity of myelofibrosis, and points to several interesting copy number aberrations and genes with diagnostic and prognostic impact.


Asunto(s)
Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Deleción Cromosómica , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Pronóstico , Análisis de Secuencia de ADN
2.
Haematologica ; 98(4): 576-83, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23065512

RESUMEN

Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum.


Asunto(s)
Anemia Refractaria/genética , Anemia Sideroblástica/genética , Leucemia Mielomonocítica Crónica/genética , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Anemia Refractaria/diagnóstico , Anemia Refractaria/metabolismo , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/metabolismo , Antígenos CD34/metabolismo , Análisis por Conglomerados , Hibridación Genómica Comparativa , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Diagnóstico Diferencial , Dioxigenasas , Femenino , Perfilación de la Expresión Génica , Humanos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/metabolismo , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Ribonucleoproteínas/genética , Análisis de Secuencia de ADN , Factores de Empalme Serina-Arginina
3.
Genes Chromosomes Cancer ; 51(8): 743-55, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22489043

RESUMEN

Since the discovery of the JAK2V617F tyrosine kinase-activating mutation several genes have been found mutated in nonchronic myeloid leukemia (CML) myeloproliferative neoplasms (MPNs), which mainly comprise three subtypes of "classic" MPNs; polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We searched for mutations in ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 genes in 149 non-CML MPNs, including 127 "classic" MPNs cases. JAK2 was mutated in 100% PV, 66% ET and 68% MF. We found a high incidence of ASXL1 mutation in MF patients (20%) and a low incidence in PV (7%) and ET (4%) patients. Mutations in the other genes were rare (CBL, DNMT3A, IDH2, MPL, SF3B1, SUZ12, NF1) or absent (IDH1).


Asunto(s)
Proteínas de Unión al ADN/genética , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Portadoras/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Análisis Mutacional de ADN , Dioxigenasas , Femenino , Humanos , Isocitrato Deshidrogenasa/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias , Neurofibromina 1/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Complejo Represivo Polycomb 2 , Proteínas Proto-Oncogénicas c-cbl/genética , Factores de Empalme de ARN , Receptores de Trombopoyetina/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Factores de Transcripción
4.
BMC Cancer ; 12: 304, 2012 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-22823977

RESUMEN

Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach.


Asunto(s)
Leucemia Mieloide/genética , Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Transformación Celular Neoplásica/genética , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/terapia , Modelos Biológicos , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/terapia
5.
Am J Hematol ; 87(7): 659-62, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22535592

RESUMEN

To determine whether the distinct and heterogeneous WHO category called "AML with myelodysplasia-related changes" (MRC-AML), presents specific molecular alterations we searched for mutations in genes known to be mutated in malignant myeloid diseases. In 48 MRC-AML patients analyzed, we found 17 mutations in ASXL1 (35%), eight in RUNX1 (17%), seven in TET2 (15%), 12 in IDH (n = 2) or IDH2 (n = 10) (25%), four in DNMT3A (8%), four in NPM1 (8%), and one in FLT3 (2%). Mutations were more frequent in the intermediate cytogenetic (IC) subgroup of 36 patients than in the unfavorable karyotype subgroup, with an average ratio mutations/patients of 1.36 [0-3] vs. 0.33 [0-2] (P < 0.001). Then, we compared these 36 patients with IC MRC-AML with a control panel of 37 no-MRC-AML patients, who had both IC and no dysplasia. IC MRC-AMLs were associated with higher incidence of ASXL1 mutations (47% vs. 0%, P < 0.001) and lower incidence of DNMT3A (6% vs. 38%, P = 0.001), NPM1 (11% vs. 62%, P < 0.001) and FLT3 (3% vs. 49%, P < 0.001) mutations. No difference was found in the incidence of IDH1/2 or TET2 mutations according to the presence of dysplasia. Complete remission rate after intensive treatment was lower in the MRC-AML group than in the no-MRC-AML group (48% vs. 78%, P = 0.023) and in wild type NPM1 patients (50% vs. 84%, P = 0.009). Our study showed that MRC-AML as defined in the WHO 2008 classification presents a specific mutation pattern characterized by a high frequency of ASXL1 mutations and a low rate of NPM1, FLT3, and DNMT3A mutations.


Asunto(s)
Médula Ósea/patología , ADN Intergénico/química , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Tasa de Mutación , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Femenino , Francia , Estudios de Asociación Genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Inducción de Remisión , Proteínas Represoras/metabolismo , Organización Mundial de la Salud , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
6.
Oncotarget ; 6(10): 8388-96, 2015 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-25860933

RESUMEN

Acute myeloid leukemias (AML) with myelodysplasia-related changes (AML-MRC) are defined by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previous MDS. The goal of this study was to identify distinct biological and prognostic subgroups based on mutations of ASXL1, RUNX1, DNMT3A, NPM1, FLT3 and TP53 in 125 AML-MRC patients according to the presence of MLD, cytogenetics and outcome. ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030). TP53 mutations (n=28, 22%) were mostly found in complex karyotype AML (26/28) and predicted poor outcome within unfavorable cytogenetic risk AML (mutant vs. wild-type: 9% vs. 40%, p=0.040). In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS. We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis. This could be useful for future diagnostic and prognostic classifications.


Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Proteínas Represoras/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/patología , Nucleofosmina , Pronóstico , Proteínas Represoras/metabolismo , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/metabolismo , Adulto Joven
7.
J Hematol Oncol ; 5: 12, 2012 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-22436456

RESUMEN

The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment.


Asunto(s)
Enfermedades de la Médula Ósea/clasificación , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Mutación , Proteínas Represoras/genética , Análisis Mutacional de ADN , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Modelos Biológicos , Mutación/fisiología , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Pronóstico
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