Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia

Sci Transl Med. 2015 Jun 10;7(291):291ra96. doi: 10.1126/scitranslmed.aaa5731.

Abstract

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations resulting in constitutive kinase activity are common in acute myeloid leukemia (AML) and carry a poor prognosis. Several agents targeting FLT3 have been developed, but their limited clinical activity suggests that the inhibition of other factors contributing to the malignant phenotype is required. We examined gene expression data sets as well as primary specimens and found that the expression of GLI2, a major effector of the Hedgehog (Hh) signaling pathway, was increased in FLT3-ITD compared to wild-type FLT3 AML. To examine the functional role of the Hh pathway, we studied mice in which Flt3-ITD expression results in an indolent myeloproliferative state and found that constitutive Hh signaling accelerated the development of AML by enhancing signal transducer and activator of transcription 5 (STAT5) signaling and the proliferation of bone marrow myeloid progenitors. Furthermore, combined FLT3 and Hh pathway inhibition limited leukemic growth in vitro and in vivo, and this approach may serve as a therapeutic strategy for FLT3-ITD AML.

Publication types

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

MeSH terms

  • Animals
  • Cell Compartmentation
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Progression
  • Drug Synergism
  • Gene Duplication / drug effects
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mutant Proteins / metabolism*
  • Myeloproliferative Disorders / pathology
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Nuclear Proteins / metabolism
  • Phenylurea Compounds / pharmacology
  • Receptors, G-Protein-Coupled / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction* / drug effects
  • Smoothened Receptor
  • Sorafenib
  • Stem Cells / cytology
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein Gli2
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • GLI2 protein, human
  • Hedgehog Proteins
  • IPI-926
  • Kruppel-Like Transcription Factors
  • Mutant Proteins
  • Nuclear Proteins
  • Phenylurea Compounds
  • Receptors, G-Protein-Coupled
  • STAT5 Transcription Factor
  • Smo protein, mouse
  • Smoothened Receptor
  • Veratrum Alkaloids
  • Zinc Finger Protein Gli2
  • Niacinamide
  • Sorafenib
  • fms-Like Tyrosine Kinase 3

Associated data

  • GEO/GSE67134