MYELOID NEOPLASIA PAK 1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

• Targeting of PAK1 inhibits primary AML and MDS patients’ cells including leukemia stem cells but spares healthy stem and progenitor cells. • Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes. Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)hasbeenattributed to failureofcurrentchemotherapeutic regimens totarget leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector moleculeofH2.0-likehomeobox (HLX), agene functionally relevant forAMLpathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads toprofound leukemia inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of the MYC oncogene and a core network of MYC target genes. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Moreover, we find thatPAK1 upregulation occurs during disease progression and is relevant for patient survival in MDS. 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. (Blood. 2015;126(9):1118-1127)