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

Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.

Author information

1
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Infinity Pharmaceuticals, Cambridge, MA 02139, USA.
3
Cancer Developmental Biology, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
4
Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
5
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
6
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
7
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. matsuwi@jhmi.edu.

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.

PMID:
26062848
PMCID:
PMC4644635
DOI:
10.1126/scitranslmed.aaa5731
[Indexed for MEDLINE]
Free PMC Article

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