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Blood ; 129(6): 667-679, 2017 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-28028029


The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.

Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Mutación , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Calreticulina/genética , Calreticulina/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Policitemia Vera/metabolismo , Policitemia Vera/fisiopatología , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/fisiopatología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Receptores de Trombopoyetina/genética , Receptores de Trombopoyetina/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Trombocitemia Esencial/metabolismo , Trombocitemia Esencial/fisiopatología
Blood ; 128(8): 1121-8, 2016 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-27365426


We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.

Predisposición Genética a la Enfermedad , Células Germinativas/metabolismo , Hematopoyesis/genética , Janus Quinasa 2/genética , Mutación/genética , Trastornos Mieloproliferativos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Demografía , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados , Adulto Joven
Iran J Basic Med Sci ; 18(10): 967-73, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26730330


OBJECTIVES: Nitric oxide (NO), a product of inducible nitric oxide synthase (iNOS), contributes in germ cell apoptosis. This study was aimed to evaluate the effects of Aloe vera gel (AVG) on male Wistar rat reproductive organ, serum NO level, and expression of iNOS gene in leydig cells. MATERIALS AND METHODS: Adult male Wistar rats (n=36) were used for experiments in three groups. The experimental groups were orally administered with the AVG extract solution once-daily as follow: 150; group A, 300; group B, and only normal saline; group C (control group). They were mated with untreated females and the reproductive and chemical parameters were assessed for each group, including semen quality, serum testosterone, sperm fertility, gonad and body weight, serum NO concentration (by the Griess method), and iNOS gene expression (using RT-PCR). RESULTS: The testes weight, serum testosterone, as well as sperm count and fertility of the AVG treated groups were significantly reduced when compared to the control (P<0.001). Concentration of serum NO was significantly increased (37.1±4.63 µM) in the administrated group with higher AVG concentration, compared to the control group (P<0.001; 10.19±0.87 µM); however, iNOS mRNA expression was increased in the treated animals (P<0.001). CONCLUSION: iNOS may play a functional role in spermatogenesis via apoptosis, reducing sperm count, but further studies are needed to illustrate the mechanisms by which AVG exerts its negative effects on spermatogenesis and sperm quality.