A blockade of leukotriene-mediated Alox5 function provides a new strategy for the treatment of JAK2V617F-induced polycythemia vera

Abstract

Polycythemia vera (PV) is a hematopoietic stem cell disorder characterized by JAK2V617F, a mutation that gives rise to erythrocytosis. Our previous studies have shown that arachidonate 5-lipoxygenase (Alox5) is a critical driver in PV and the inhibition of the Alox5 pathway attenuates JAK2V617F-induced PV development in mice. However, the molecular mechanism underlying the function of Alox5 in PV remains elusive. It is well established that leukotrienes are important downstream molecules synthesized through the Alox5 pathway in leukocytes and play a key role in mediating Alox5 functions in human asthma. In this study, we found that Montelukast, a leukotriene receptor antagonist, inhibits cell proliferation and induces apoptosis in JAK2V617F-cell lines. Further in vivo studies demonstrated that Montelukast treatment suppresses the development of PV induced by JAK2V617F in mice, comparable to the effect of Alox5 inhibition on PV development. Notably, the inhibitory effect of Montelukast on PV is dependent on selectively eradicating PV stem cells while sparing their normal counterparts. Moreover, we found that Montelukast synergizes with the JAK2 inhibitor (ruxolitinib) to inhibit proliferation of JAK2V617F-expressing hematopoietic cells in vitro and in JAK2V617F mice. Finally, we showed that Montelukast induces caspase-3- and PARP-associated apoptosis of JAK2V617F-expressing cells. These findings indicate that Montelukast is a promising candidate agent and could be combined with an JAK2 inhibitor (such as ruxolitinib) for PV treatment.