The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells
Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and chance of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in people are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. People from the PIM group of serine/threonine kinases are caused by JAK/STAT signaling, regulate hematopoietic stem cell growth, safeguard hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming qualities. We hypothesized that PIM kinases offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells in addition to primary MPN patient cells using the PIM kinase inhibitors SGI-1776 and AZD1208 and also the JAK2 inhibitor ruxolitinib. While MPN model cells somewhat insensitive to PIM inhibitors, mixture of PIM inhibitors with ruxolitinib brought to some synergistic impact on MPN cell growth because of SGI-1776 enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically covered up, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was connected with activation of BAD, inhibition of downstream aspects of the mTOR path, including p70S6K and S6 protein, and activation of 4EBP1. Importantly, PIM inhibitors re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis. Finally, exogenous expression of PIM1 caused ruxolitinib resistance in MPN model cells. These data indicate that PIMs are likely involved in MPNs which mixing PIM and JAK2 kinase inhibitors offer a far more effective therapeutic method for MPNs over JAK2 inhibitor mono-therapy.