Jak2V617F myeloproliferative neoplasm stem cells and interferon-alpha

The myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis that arise as a result of aberrant activation of tyrosine kinases and result in the proliferation and accumulation of mature myeloid cells in the blood, bone marrow and spleen. The prototypical MPN, chronic myeloid leukemia (CML) is caused by constitutive activation of ABL kinase occurring as a result of the BCR-ABL fusion. Importantly, targeted therapy to inhibit ABL kinase signaling, using imatinib, induces durable clinical responses in the majority of CML patients. The molecular pathogenesis of the BCRABL negative MPNs, polycythemia vera (too many red cells), essential thrombocythemia (too many platelets) and myelofibrosis, was elucidated in 2005 with the discovery of JAK2V617F, an activating mutation in the non-receptor tyrosine kinase, JAK2 [1]. The JAK2V617F mutation is present in more than 95% patients with polycythemia vera, and approximately 50% patients with essential thrombocythemia and myelofibrosis. In advanced disease, MPN may transform to acute leukaemia and this is associated with a dismal prognosis. In MPN, JAK2V617F is found in long-term hematopoietic stem cells (LT-HSCs), a population of rare quiescent cells present in the bone marrow and capable of long-term self-renewal. These somatically mutated LTHSCs, referred to as MPN-propagating cells or MPN stem cells, maintain the MPN throughout the life of the patient and can serially transplant disease in animal models of Jak2V617F-mediated MPN [2, 3]. To definitively cure MPN will require complete eradication of the MPN disease-maintaining stem cell population. In contrast to the efficacy of imatinib in achieving molecular remissions in CML, JAK2 kinase inhibitors have shown only modest benefit in the treatment of myelofibrosis, namely in reducing splenomegaly and improving constitutional symptoms. Furthermore, the lack of an effect of the JAK2 inhibitors on reducing JAK2V617F allele burden in myelofibrosis patients [4] and the demonstration that MPN-propagating cells are insensitive to JAK2 kinase inhibition in vivo [2] suggests that MPN stem cells do not require JAK2 signaling for survival and that JAK2 inhibitor monotherapy will not cure MPN patients. The clinical efficacy of long-acting pegylated IFNα in MPN has renewed interest in understanding the mechanism of action of IFNα treatment in JAK2V617Fmediated MPN. Prolonged IFNα treatment results in normalization of blood counts in most patients with polycythemia vera, reduces JAK2V617F allele burden and in 15-40% of patients, the JAK2V617F mutant clone is rendered undetectable to sensitive molecular assays[5,