Familial Essential Thrombocythemia Showing Spontaneous Megakaryocyte Colony Formation and Acquired JAK2 Mutations without a Germline Mutation in C-MPL or TPO.

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder, characterized by increased proliferation of megakaryocytes and elevated platelet counts that usually occurs sporadically. We report a family with 7 affected individuals in three generations, including one individual with a phenotype resembling polycythemia vera, a related disorder. Megakaryocyte (CFU-MK) colony formation occurred in the absence of added cytokines in cultures of peripheral blood from affected family members. Some reports of familial ET have identified mutations in the genes coding for thrombopoietin (TPO), the cytokine that primarily regulates platelet production and its receptor, c-MPL. In this family, the MPL gene was excluded by linkage analysis. Although TPO levels were elevated in most affected family members and evidence for linkage was found between the disease and TPO (𝛉 = 0.0, Zmax = 3.0), a TPO mutation was not identified by DNA sequencing. The JAK2 V617F mutation that has been associated with 50% of sporadic cases of ET was identified as a somatic mutation in the peripheral blood of the two most clinically affected family members. These patients also had the most elevated TPO levels, raising the possibility of an association between JAK2 and TPO production. Further study of familial myeloproliferative diseases will help elucidate the initiating genetic events underlying ET.