Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with somatic mutations of JAK2 and, in few instances, of LNK and characterized by increased red blood cell production. The clinical course of this MPN typically includes a pre-polycythemic phase characterized by borderline erythrocytosis and thrombocytosis, an overt polycythemic phase with trilineage hyperplasia, and eventually post-PV myelofibrosis (MF). Acute myeloid leukemia (AML) may occur as a result of additional somatic mutations. About 95% of patients with PV carry the unique V617F mutation in JAK2 exon 14, while several mutations in JAK2 exon 12 have been described in the minority of JAK2 (V617F)-negative subjects. In some patients JAK2 (V617F) and JAK2 exon 12 can coexist as two separate clones. We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders