Mutational Analysis of Thrombopietin, c-MPL and Jak2 Genes in Essential Thrombothethymia Patients - Identification of Concurrent Mutations of c-MPL and Jak2.

The molecular pathogenesis in chronic myeloproliferative disorder including essential thrombocythemia (ET) has been recently clarified. We previously identified a novel activating mutation of c-MPL gene (S505N) as a cause of familial ET. The Jak2 mutation (Jak2V617F) is also reported most frequently as a constitutive activating mutation in ET. Here we screened the mutations in the open reading frames of thrombopoietin (TPO), c-MPL and Jak2 in the 26 Japanese (sporadic) ET patients. None had any somatic mutations in TPO. We found Jak2V617F mutation in 7 patients. Interestingly, one of the patients had the c-MPL somatic mutation (W515L). The c-MPL W515L transfectants presented the autonomous STAT5 and MEK1/2 phosphorylation in the absence of the ligand, which show the c-MPL W515L is a constitutive activating mutation for signalling. The concurrent mutations of Jak2V617F and c-MPL W515L are likely to contribute to the pathogenesis of the thrombocythemia in this patient. Now we are focusing on the issue whether the single clone with both of two mutations occupy or the two clones with either Jak2 or c-MPL mutation coexist in the bone marrow of this ET patient (Single cell PCR is on going with the megakaryocytes of this patient).