title: PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome.
abstract: 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 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 that PAK1 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.
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Ashley
authors.initials: A
authors.lastname: Pandolfi
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Robert F
authors.initials: RF
authors.lastname: Stanley
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Gopichand
authors.initials: G
authors.lastname: Pendurti
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Kira
authors.initials: K
authors.lastname: Gritsman
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Departments of Cell Biology and of Medicine, Division of Hemato-Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016259:Genes, myc; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D034622:RNA Interference; D000067492:RNAi Therapeutics; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases