Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2V617F allele burden correlates.

Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
European Journal Of Haematology (Impact Factor: 2.41). 03/2008; 80(3):197-200. DOI: 10.1111/j.1600-0609.2007.01003.x
Source: PubMed

ABSTRACT The prognostic significance of cytogenetic findings at diagnosis in polycythemia vera (PV) was investigated in a retrospective series of 137 patients. Cytogenetics were normal in 117 patients (85%) and displayed a -Y abnormality in five patients (7% of male patients), and other chromosomal abnormalities in 15 patients (11%). The most frequent cytogenetic anomalies were trisomy 8 (n = 4), trisomy 9 (n = 2), deletion 20q (n = 2) and chromosomal 1 abnormalities (n = 2). Parameters that were significantly associated with abnormal cytogenetics included age > or = 60 yr (P = 0.02), but not JAK2V617F allele burden, thrombosis, hemorrhage, leukemic/fibrotic transformation, or survival. We conclude that cytogenetic anomalies occur infrequently at PV diagnosis and do not confer an adverse outcome.

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    ABSTRACT: The myeloproliferative neoplasms (MPNs), as defined by the latest World Health Organisation’s (WHO) revision, include a range of clonal haematopoietic disorders that are characterised by an increase in the number of one or more mature blood cell progeny. Classical cytogenetic analysis has played a crucial role in the identification of important oncogenes in many haematological malignancies, the paradigm being the identification of the t(9;22) in chronic myeloid leukaemia. This discovery led not only to the elucidation of the pathogenetic role of the bcr-abl fusion gene, but also to the development of effective targeted therapy. Other oncogenic events, involving the activation of different tyrosine kinases, were subsequently identified by the study of rare translocations. In contrast, the pathogenesis of the Philadelphia-negative MPNs namely, essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), as well as chronic neutrophilic leukeamia (CNL), has not been greatly advanced by karyotypic analysis. Nevertheless, cytogenetic analysis still has a role in the routine investigation of such patients, as an abnormal profile provides evidence of clonality: a factor recognised by the WHO diagnostic criteria (Table 3.1). In addition, cytogenetic analysis may also provide valuable prognostic information in PMF, assist in the selection of specific therapy and ensure the exclusion of related disorders that may be associated with marrow fibrosis (see review [1]). The aim of this chapter is to review the current knowledge of chromosomal abnormalities in the MPN and to highlight possible pathogenetic consequences of such changes. KeywordsCytogenetics-Pathogenesis-Prognosis-Primary myelofibrosis-Polycythemia vera-Essential thrombocythemia
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    ABSTRACT: The JAK2(V617F) mutation is frequently observed in classical myeloproliferative disorders, and disease progression is associated with a biallelic acquisition of the mutation occurring by mitotic recombination. In this study, we examined whether JAK2 activation could lead to increased homologous recombination (HR) and genetic instability. In a Ba/F3 cell line expressing the erythropoietin (EPO) receptor, mutant JAK2(V617F) and, to a lesser extent, wild-type (wt) JAK2 induced an increase in HR activity in the presence of EPO without modifying nonhomologous end-joining efficiency. Moreover, a marked augmentation in HR activity was found in CD34(+)-derived cells isolated from patients with polycythemia vera or primitive myelofibrosis compared with control samples. This increase was associated with a spontaneous RAD51 foci formation. As a result, sister chromatid exchange was 50% augmented in JAK2(V617F) Ba/F3 cells compared with JAK2wt cells. Moreover, JAK2 activation increased centrosome and ploidy abnormalities. Finally, in JAK2(V617F) Ba/F3 cells, we found a 100-fold and 10-fold increase in mutagenesis at the HPRT and Na/K ATPase loci, respectively. Together, this work highlights a new molecular mechanism for HR regulation mediated by JAK2 and more efficiently by JAK2(V617F). Our study might provide some keys to understand how a single mutation can give rise to different pathologies.
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    ABSTRACT: The frequency of cytogenetic abnormalities in the Philadelphia-negative myeloproliferative neoplasms (MPNs) varies from approximately 30% in primary myelofibrosis (PMF) to less than 5% in essential thrombocytosis (ET). The spectrum of aberrations is heterogeneous, ranging from gains and losses of genetic material to structural changes including unbalanced translocations. However, no specific abnormality has been identified to date. Nevertheless, such investigations can provide evidence of clonality and, as a result, cytogenetic findings have been included in the WHO diagnostic criteria for this group of diseases. The aim of the current review is to discuss the pathogenetic insight and prognostic information that standard, as well as molecular cytogenetic analysis has provided. A brief overview is given of the cytogenetic findings in the individual diseases, followed by a more detailed discussion of the possible pathogenetic consequences of specific abnormalities and their impact on prognosis.
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