Abstract
Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and risk of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in patients are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. Members of the PIM family of serine/threonine kinases are induced by JAK/STAT signaling, regulate hematopoietic stem cell growth, protect hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming properties. We hypothesized that PIM kinases may offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells as well as primary MPN patient cells with the PIM kinase inhibitors SGI-1776 and AZD1208 and the JAK2 inhibitor ruxolitinib. While MPN model cells were rather insensitive to PIM inhibitors, combination of PIM inhibitors with ruxolitinib led to a synergistic effect on MPN cell growth due to enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically suppressed, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was associated with activation of BAD, inhibition of downstream components of the mTOR pathway, 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 induced ruxolitinib resistance in MPN model cells. These data indicate that PIMs may play a role in MPNs and that combining PIM and JAK2 kinase inhibitors may offer a more efficacious therapeutic approach for MPNs over JAK2 inhibitor mono-therapy.
Highlights
Myeloproliferative neoplasms were first recognized in 1951 and today, classical Philadelphia chromosomenegative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1, 2]
We treated MPN model cell lines, including JAK2-V617F-positive HEL, Uke1, and SET2 cells, and BAF3 cells that are transformed by the expression of JAK2-V617F (BaF3-JAK2-V617F), with AZD1208 and again saw little effect on cell growth and viability (Fig. 1B and not shown)
This suggested that perhaps PIMs may not play a critical role in the growth of these MPN cell lines, which are dependent on signaling by JAK2-V617F
Summary
Myeloproliferative neoplasms were first recognized in 1951 and today, classical Philadelphia chromosomenegative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1, 2]. These neoplasms are clonal hematopoietic stem/ progenitor cell diseases that lead to a combination of erythrocytosis, thrombocytosis, leukocytosis, and scarring of the bone marrow [3]. While the ability of mutant CalR to activate STAT5 signaling is not completely clear, such cells do express a gene expression profile consistent with activation of the JAK2-STAT5 pathway as in JAK2mutant positive MPNs [11]. While this genetic data alone suggests JAK2 activation plays an etiologic role in MPNs, a plethora of mouse models have demonstrated that expression of JAK2-V617F, as well as other JAK2activating mutations found in MPNs, can generate human MPN-like phenotypes in mice [8, 9, 12,13,14,15,16,17,18,19]
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