Cytogenetics, JAK2 and MPL mutations in polycythemia vera, primary myelofibrosis and essential thrombocythemia

Abstract

BackgroundThe detection of molecular and cytogenetic alterations is important for the diagnosis, prognosis and classification of myeloproliferative neoplasms.ObjectivesThe 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.MethodsTwenty 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.ResultsChromosomal 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.ConclusionsThis 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.

High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis

“…The GATA family is essential to the development of many cell lineages, including hematopoietic, cardiac, and endodermal. GATA1 , GATA2 , and GATA3 are needed for normal hematopoiesis, and their mutations are implicated on a variety of blood disorders, including MF [Dos Santos et al, 2011;Hahm et al, 2015;Mehrotra et al, 2015].…”

Identification of JAK2V617F Mutation on Myeloproliferative Disorders in Medan

“…Conversely, other mutations such as TET2 or IDH mutations are occasionally seen in PV and ET [19,20,21]. Based on previous study, the JAK2 V617F mutation was detected in 18/20 (90%) cases of PV, 9/21 (42.9%) of PMF and 8/17 (47.1%) of ET [22].…”

Myeloid Neoplasms

“…The abnormal promyelocytes lack CD10 and CD16, which are mature myeloid markers. It has been reported that the combination of the absence of CD11b, CD11c, and HLA DR identifies 100% of APLs [5]. CD2 positivity is a feature of APL.…”

“…Mutations in these genes confer activation of the JAKÀSTAT pathway (STAT: signal transducer and activator of transcription-a gene regulatory protein) and other pathways promoting differentiation and proliferation of various lineages. The JAK2ÀV617 mutation is present in approximately 95% of patients with PV, in 58% patients with primary myelofibrosis, and in 50% of patients with essential thrombocythemia [5]. Various characteristics and diagnostic features of these diseases are summarized in Table 6.1.…”