Inhibition of PAK1 generates an ameliorative effect on MPLW515L mouse model of myeloproliferative neoplasms by regulating the differentiation and survival of the megakaryocytes

Most Thrombopoietin Receptor (MPL) mutations result in abnormal megakaryocyte expansion in the spleen or bone marrow (BM), leading to progressive fibrosis. It has been reported that p21 (RAC1)-activated kinase 1 (PAK1) participates in the proliferation and differentiation of megakaryoblast, PAK1 phosphorylation was found to be increased in patients with myeloproliferative neoplasm (MPNs) and murine MPN cells with the MPLW515L mutant gene in the present study; however, the function of the over activated PAK1 in MPN cells remains unclear. We found that inhibition of PAK1 caused significant changes in the biological behaviors of MPLW515L mutant cells in vitro, including arrested growth or reduced clonality as well as increased polyploid DNA and cells Apoptosis due to upregulated cleaved Caspase 3. In vivo, PAK1 Inhibitor treatment caused a slow elevation of leukocytosis and hematocrit (HCT) and reduction in hepatosplenomegaly in 6133/MPLW515L transplanted mice, along with reduced tumor cell infiltration and prolonged survival. Further deletion of PAK1 sustained a relatively normal HCT and platelet count at the beginning of disease but did not completely alleviate the splenomegaly of MPLW515L mutant mice. Notably, PAK1 knockout attenuated the destruction of splenic structure, and reduced the megakaryocyte burden within the BM. These results suggest that the inhibition of PAK1 may be a considerable method treating MPLW515L mutant MPN by intervening megakaryocytes.

MPLW515L mutation; PAK1 inhibition; apoptosis; growth; megakaryocytes; survival.