Hypoxia inhibits JAK2V617F activation via suppression of SHP-2 function in myeloproliferative neoplasm cells

Abstract

The hypoxic microenvironment of the bone marrow, known as the hypoxic niche, supports hematopoietic stem cell quiescence and maintains long-term repopulation activity. Hypoxia also affects the expansion of progenitor cells and enhances erythropoiesis and megakaryopoiesis. In contrast to the known effects of hypoxia on normal hematopoiesis, the effects of the hypoxic environment of the bone marrow on the pathogenesis of myeloproliferative neoplasms (MPNs) have not been well studied. In the present study, we investigated the role of the hypoxic environment in the pathophysiology of MPNs, focusing on JAK2V617F, a major driver of mutation in Philadelphia-negative MPNs. We found that the activity of JAK2V617F was suppressed in hypoxic conditions not only in JAK2V617F-positive leukemia cells, but also in primary peripheral blood mononuclear cells from patients with polycythemia vera. Concomitant with the inhibition of JAK2V617F activity, hypoxia increased the expression of p27/KIP1, the primary negative regulator of the cell cycle, and inhibited cell cycle progression in JAK2V617F-positive leukemia cell lines. The spontaneous erythroid colony formation of primary cells from polycythemia vera patients was also suppressed under hypoxic conditions. We also revealed that the hypoxia-induced overproduction of reactive oxygen species played a crucial role in the inhibition of JAK2V617F through the oxidation and inhibition of SHP-2, a protein tyrosine phosphatase that contains SH-2, which is required for JAK2 activation. In conclusion, a hypoxic environment may modulate JAK2-positive MPN cell fate and disease progression through the suppression of SHP-2 function and the subsequent suppression of JAK2V617F activity.