Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Cell Rep. 2014 Nov 20;9(4):1333-48. doi: 10.1016/j.celrep.2014.10.039. Epub 2014 Nov 13.

Abstract

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mastocytosis, Systemic / pathology
  • Mice, Inbred C57BL
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Phenylurea Compounds / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-kit / metabolism*
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Survival Analysis
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • fms-Like Tyrosine Kinase 3 / metabolism*
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Benzothiazoles
  • Guanine Nucleotide Exchange Factors
  • Mutant Proteins
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • STAT5 Transcription Factor
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Tiam1 protein, mouse
  • quizartinib
  • Proto-Oncogene Proteins c-kit
  • fms-Like Tyrosine Kinase 3
  • Focal Adhesion Protein-Tyrosine Kinases
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein