Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies

Abstract

Most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation. Approximately 96% of patients with polycythemia vera (PV) harbors the V617F mutation in JAK2 exon 14, whereas the minority of JAK2 (V617F)-negative subjects shows several mutations in exon 12. Other mutation events as MPL, TET2, LNK, EZH2 have been described in chronic phase, while NF1, IDH1, IDH2, ASX1, CBL and Ikaros in blast phase of MPN. The specific pathogenic implication of these mutations is under investigation, but they may have a role in refinement of diagnostic criteria and in development of new prognostic models. Several trials with targeted therapy (JAK inhibitors) are ongoing mostly involving patients with PMF, post-PV MF and post-essential thrombocythemia (ET) MF. Treatment with ruxolitinib and TG101348 has shown clinically significant benefits, particularly in improvement of splenomegaly and constitutional symptoms in MF patients. On the other hand, JAK inhibitors have not thus far shown disease-modifying activity therefore any other deduction on these new drugs seems premature.

Figure 1. Natural history of myeloproliferative neoplasms

Most frequent clinical complications in MPN patients are thrombosis, whereas hemorrhage is above all observed in essential thrombocythemia (ET) patients. ET may slowly develop into polycythemia vera (PV), especially if it carries the JAK2 (V617F) mutation. PV and ET may progress to myelofibrosis (post-ET, post-PV MF) and then turn into acute myeloid leukemia (AML), although they may evolve into AML even without showing a MF phase.

Figure 2. MPN mutations activating STAT3/5

Mutations of JAK2, MPL and CBL (due to gain of function) and mutations of LNK and NF1 (due to loss of function) activate STAT3/5 which, through nuclear signal transduction, determines an amplification of immune response, inflammation, angiogenesis and proliferation, mostly modulated by higher circulating cytokines levels. STAT3/5 activation also confers resistance to apoptosis which promotes and supports myeloid precursor proliferation.