PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Ashley Pandolfi, Robert F. Stanley, Yiting Yu, Boris A. Bartholdy, Gopichand Pendurti, Kira Gritsman, Jacqueline Boultwood, Jonathan Chernoff, Amit K. Verma, Ulrich G. Steidl

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1118-1127
Number of pages10
JournalBlood
Volume126
Issue number9
DOIs
StatePublished - Aug 27 2015

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Myelodysplastic Syndromes
Stem cells
Acute Myeloid Leukemia
Genes
p21-Activated Kinases
Molecules
Stem Cells
RNA
Apoptosis
Homeobox Genes
Myeloid Cells
Therapeutics
RNA Interference
Oncogenes
Disease Progression
Leukemia
Up-Regulation
Down-Regulation
Survival
Population

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. / Pandolfi, Ashley; Stanley, Robert F.; Yu, Yiting; Bartholdy, Boris A.; Pendurti, Gopichand; Gritsman, Kira; Boultwood, Jacqueline; Chernoff, Jonathan; Verma, Amit K.; Steidl, Ulrich G.

In: Blood, Vol. 126, No. 9, 27.08.2015, p. 1118-1127.

Research output: Contribution to journalArticle

Pandolfi, Ashley ; Stanley, Robert F. ; Yu, Yiting ; Bartholdy, Boris A. ; Pendurti, Gopichand ; Gritsman, Kira ; Boultwood, Jacqueline ; Chernoff, Jonathan ; Verma, Amit K. ; Steidl, Ulrich G. / PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. In: Blood. 2015 ; Vol. 126, No. 9. pp. 1118-1127.
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