PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Poor clinical outcome of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia-inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC oncogene and a core network of MYC target genes. Moreover, we find that PAK1 up-regulation occurs during disease progression and is relevant for patient survival in MDS. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Our studies highlight PAK1 as a novel target in AML and MDS, and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases. To obtain insight into the molecular mechanism for the induction of apoptosis and differentiation resulting from PAK1 inhibition in AML, we performed gene expression microarrays following treatment with either IPA-3 or FRAX-597. RNA was isolated from THP-1 cells after 5 hours of treatment with IPA-3 (6 ug/mL), FRAX-597 (2 ug/mL) or an equal volume of DMSO using Trizol Reagent (Invitrogen).