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.
"Trisomy 9 is present in 10% of PMF, PV and ET cases.(12,14) The prognosis of patients with this alteration is controversial in terms of survival and evolution of the disease, but more recent studies have shown that this abnormality is a sign of worse prognosis in PMF.(13,15) "
[Show abstract][Hide abstract] ABSTRACT: The detection of molecular and cytogenetic alterations is important for the diagnosis, prognosis and classification of myeloproliferative neoplasms.
THE AIM OF THIS STUDY WAS TO DETECT THE FOLLOWING MUTATIONS: JAK2 V617F, JAK2 exon 12 and MPL W515K/L, besides chromosomal abnormalities. Furthermore, molecular and cytogenetic alterations were correlated with the leukocyte and platelet counts, hemoglobin levels and age in all patients and with the degree of fibrosis in primary myelofibrosis cases.
Twenty cases of polycythemia vera, 17 of essential thrombocythemia and 21 of primary myelofibrosis were selected in the Hematology Department of the Universidade Federal de São Paulo (UNIFESP) between February 2008 and December 2009. The JAK2 V617F, JAK2 exon 12 mutations, MPL W515K and MPL W515L mutations were investigated by real-time PCR and direct sequencing. G-band karyotyping and fluorescence in situ hybridization were used to detect chromosomal abnormalities.
Chromosomal abnormalities were observed only in polycythemia vera (11.8%) and primary myelofibrosis cases (17.6%), without correlation to clinical data. Chromosomal abnormalities were not detected by fluorescence in situ hybridization. The JAK2 V617F mutation was observed in polycythemia vera (90%), primary myelofibrosis (42.8%) and essential thrombocythemia (47%). Patients with JAK2 V617F-negative polycythemia vera had lower platelet and leukocyte counts compared to V617F-positive polycythemia vera (p-value = 0.0001 and p-value = 0.023, respectively). JAK2 V617F-positive and MPL W515L-positive primary myelofibrosis cases had a higher degree of fibrosis than V617F-negative cases (p-value = 0.022). JAK2 exon 12 mutations were not detected in polycythemia vera patients. The MPL W515L mutation was observed in one case of primary myelofibrosis and in one of essential thrombocythemia. The MPL W515K mutation was not found in patients with essential thrombocythemia or primary myelofibrosis. The MPL W515L-positive patient with primary myelofibrosis had more severe anemia than other patients with primary myelofibrosis.
This study demonstrates that karyotyping for JAK2 and MPL mutations is useful in the diagnosis of myeloproliferative neoplasms. The precise pathogenetic contribution of these alterations is still unclear. However, this study adds more information about the pathophysiology of polycythemia vera, essential thrombocythemia and primary myelofibrosis.
[Show abstract][Hide abstract] 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 ). 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
[Show abstract][Hide abstract] 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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