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GENETICS OF ESSENTIAL THROMBOCYTHEMIA - A CHRONIC MYELOPROLIFERATIVE NEOPLASM

Essential thrombocythemia (ET) is one of the three non-Philadelphia-chromosome myeloproliferative neoplasms (MPN). It is considered to be of relatively benign clinical course with expected overall survival for patients approaching the one of general population. However, as a clonal disease of hematopoietic stem it can progress to myelofibrosis or transform into leukemia. It shows increased risk of hemorrhage (when platelet counts over 1 mil/ul), or propensity for thrombosis. In the last 10 years tremendous advances in detecting molecular genetic defects responsible for MPN, including ET were made. The most important are acquired valine to phenylalanine substitution at aminoacid 617 of the JAK2 (Janus Kinase 2) protein (JAK2V617F) that leads to constitutive activation of the tyrosine kinase, increased kinase activity and hyper-responsiveness to cytokine signaling and cell proliferation. This mutation is present in 60% of ET, >97% of PV and in around 50% of patients with PMF. The thrombopoietin receptor (c-MPL) is another oncogene in ET with W515L mutation that induces constitutive, cytokine-independent activation of the JAK-STAT pathway. MPLW515L or MPLW515K mutations are present in patients with PMF or ET at a frequency of approximately 8% and 3%, respectively, not found in PV. The recent important genetic discovery is description of Calreticulin (CALR1) mutation in 30-38% of non-Jak2/non-c-MPL mutated ETs. The del/ins mutation in the gene C-terminus or this intracellular protein chaperone and calcium controller is clinically associated with favorable prognosis if not occurring with other secondary hits, e.g. ASXL1 mutation.

chronic myeloproliferative neoplasms; essential thrombocythemia; genetics

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