Targetingof PIM1 KinaseinMyeloproliferative NeoplasmsInduced by JAK2V617F
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AbstractMyeloproliferative neoplasms (MPNs) arestem cell-derivedblood disorders. The most common mutation found in MPN patients is the JAK2V617Fmutation. JAK2 is anon-receptor tyrosine kinase involved in STAT signaling. The JAK2V617F mutation is asingle amino acid substitution of a phenylalanine for valine, whichcauses JAK2 to be constitutively activated. This mutation can cause ahematopoietic transformation. Eventuallythis transformationcan lead to the development of one of thethree different Philadelphia-negative MPN diseases: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). The JAK2V617F mutationhas been identified in 95% PVpatients,and 50-60% ofETand PMF patients.A JAK1/2 inhibitor (ruxolitinib) has been approved for MF and PV patients and,though it provides initial benefits, it is not effective enough to causelong-termremission in patients. This creates a critical need to identify new therapeutic targets for MPN patients. We found that PIM1 levels were significantly increased inMPN patients, as well asour JAK2V617F mouse modelof MPN.We observedthatknockdown of PIM1 caused a significant decrease in proliferationof JAK2V617F expressing cells. We also found that PIM1 knockdownhad no effect on the proliferation of hematopoietic cells not expressing JAK2V617F, leading us to believe PIM1 is only required in JAK2V617F mediated proliferation. Pharmacological inhibition of PIM kinases,using TP-3654,(kindly provided by Tolero pharmaceuticals)also led to a significant decrease in proliferation of JAK2V617F-expressing cells, but had no effect on cellslacking the mutation. We also found thatthePIM inhibitor,TP-3654,workssynergistically with ruxolitinibto achieve an even greater decrease in proliferation. We found that using the combination of ruxolitiniband TP-3654,we could use both drugs at lower concentrations andachieve an even greater decrease in proliferation and an increase apoptosis. Furthermore,we found that inhibition of PIM kinasesusing TP-3654can resensitize ruxolitinib-resistant cells to ruxolitinibtreatment.These important findingsshow that PIM1 plays animportantrolein the proliferation of hematopoietic cells expressing the JAK2V617F mutation, but is dispensable for the maintenance of cells lacking the mutation. We also found that targeting PIM kinases with TP-3654,significantly decreasedthe proliferation, and increaseapoptosisactivationof JAK2V617Fexpressing cells. We also showedthat TP-3654 and ruxolitinibcan work synergistically. Lastly, we showed that inhibition of PIM kinases,using TP-3654,caused ruxolitinib-resistant cells tobecome resensitized toruxolitinib. These findings helpedus come to the conclusionthatPIM1 kinase, is an importanttherapeutictargetin JAK2V617F-induced MPNs.
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