JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (γ-H2Ax)–marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies

STAT1 activation in association with JAK2 exon 12 mutations

La inclusión de la perspectiva de género en la actividad jurisdiccional es una demanda sostenida de los colectivos feministas y de mujeres, dado que las sentencias tienen un poder performativo y envían un mensaje a la sociedad: “[…] tienen un poder individual y colectivo que impactan en la vida de las personas y conforman la identidad del poder judicial como un actor imprescindible en la construcción de un Estado democrático de derecho” (Suprema Corte de Justicia de la Nación, 2013:7). La incorporación de la perspectiva de género viene a garantizar la igualdad de posiciones (Kessler, 2014) entre mujeres y varones como una meta, trascendiendo la mera igualdad de oportunidades que hasta el presente se ha demostrado insuficiente para que las mujeres consigamos una ciudadanía plena. Al momento de incorporar la perspectiva de género en las sentencias, quienes juzgan deben tener presente en primer lugar, el impacto diferenciado de las normas en base al sexo de las personas. En segundo lugar, la interpretación y aplicación de las leyes en relación con (y en base a) estereotipos de género. Si, por ejemplo, quienes imparten justicia no tienen presentes los estereotipos de género vigentes detrás de las violaciones a los derechos humanos de las mujeres, si no los detectan ni cuestionan, entonces los reproducen. Tal como sostiene Scott (1996) el género es una categoría imprescindible para el análisis social. En tercer lugar, al momento del juzgamiento, se deben tener en cuenta las exclusiones legitimadas por la ley por pensar el mundo en términos binarios y androcéntricos; en cuarto lugar, la distribución no equitativa de recursos y poder que opera entre varones y mujeres en el marco de una organización social patriarcal, y, por último, el trato diferenciado por género legitimado por las propias leyes.Eje 3: Tramas violentas y espacios de exclusión.Instituto de Cultura Jurídic

STAT1 activation in association with JAK2 exon 12 mutations.

The work was supported by Leukemia and Lymphoma Research, Wellcome Trust, Medical Research Council, Kay Kendall Leukaemia Fund, Cambridge NIHR Biomedical Research Center, Cambridge Experimental Cancer Medicine Centre, Leukemia and Lymphoma Society of America and Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano; Progetto AGIMM, #1005).Due to copyright this article cannot be uploaded to the repository

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium.-- et al.The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia.1 These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone marrow¿biopsy specimens from patients with myelodysplastic syndromes show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of one or more lineages. Target genes of recurrent chromosomal aberrations have been mapped,2,3 and several genes have been identified as recurrently mutated in these disorders, including NRAS (encoding neuroblastoma RAS viral oncogene homologue), TP53 (encoding tumor protein p53), RUNX1 (encoding runt-related transcription factor 1), CBL (encoding Cas-Br-M ecotropic retroviral transforming sequence),4,5 TET2 (encoding tet oncogene family member 2),6,7 ASXL1 (encoding additional sex combs¿like protein 1),8,9 and EZH2 (encoding enhancer of zeste homologue 2).10 With the exception of TET2, most of these genes are mutated in no more than 5 to 15% of cases, and generally the mutation rates are lower in the more benign subtypes of the disease. The myelodysplastic syndromes can be divided into several categories on the basis of bone marrow and peripheral-blood morphologic characteristics and cytogenetic changes.11 In low-risk disease, such as refractory anemia, cytopenias are the major clinical challenge, whereas high-risk disease, such as refractory anemia with excess blasts, is characterized by both cytopenias and a high rate of transformation to acute myeloid leukemia. More than a quarter of patients with myelodysplastic syndromes have large numbers of ring sideroblasts in the bone marrow,12 a sufficiently distinctive morphologic abnormality to warrant a separate designation. Ring sideroblasts are characteristically seen on iron staining of bone marrow aspirates as differentiating erythroid cells with a complete or partial ring of iron-laden mitochondria surrounding the nucleus. Several genetic lesions underpinning inherited sideroblastic anemias have been identified,13 including loss-of-function mutations in the genes ALAS2 (encoding delta aminolevulinate synthase 2), ABCB7 (encoding ATP-binding cassette, subfamily B, member 7), and SLC25A38 (solute carrier family 25, member 38). The pathogenesis of ring sideroblasts in myelodysplastic syndromes, however, remains obscure, although gene-expression studies have revealed up-regulation of genes involved in heme synthesis (including ALAS2) and down-regulation of ABCB7.14,15 We reasoned that the identification of recurrently mutated cancer genes in low-grade myelodysplastic syndromes could prove useful for the diagnosis of these disorders and provide new insights into the molecular pathogenesis of these syndromesSupported by grants from the Wellcome Trust (077012/Z/05/Z, for the overall study, as well as WT088340MA, to Dr. Campbell), the Kay Kendall Leukaemia Fund, Leukemia Lymphoma Research (for the overall study and to Drs. Boultwood, Green, Vyas, and Wainscoat), the Adenoid Cystic Carcinoma Research Foundation, the Medical Research Council (MRC) (to Dr. Warren), the Oxford National Institutes for Health Research Biomedical Research Centre (to Drs. Boultwood, Vyas, and Wainscoat), the Swedish Cancer Society (to Dr. Hellstrom-Lindburg), the International Human Frontier Science Program Organization (to Dr. Varela), the Department of Veterans Affairs and the National Institutes of Health (R01-124929, P01-155249, P50- 100007, and P01-78378, to Drs. Munshi and Anderson), the Association for International Cancer Research and the Leukemia Lymphoma Society (to Drs. Warren and Green), Associazione Italiana per la Ricerca sul Cancro (to the University of Pavia, the University of Milan Bicocca, and Dr. Cazzola), and Fondazione Cariplo (to the University of Pavia and the University of Milan Bicocca).Peer Reviewe

Early drop in systolic blood pressure and worsening renal function in acute heart failure: Renal results of Pre-RELAX-AHF

Aims We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and resultsThe Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of <0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P 0.01), and Day 180 (P 0.003) mortality. ConclusionsWorsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. © 2011 The Author