title: Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.
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.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Gondek
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Hayley
authors.initials: H
authors.lastname: Ma
authors.forename: Haley
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Foerster
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Infinity Pharmaceuticals, Cambridge, MA 02139, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.affiliation: Cancer Developmental Biology, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: David Neil
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Peacock
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Bruce Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Akil A
authors.initials: AA
authors.lastname: Merchant
authors.affiliation: 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.
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. matsuwi@jhmi.edu.
authors.forename: William
authors.initials: W
authors.lastname: Matsui
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D004357:Drug Synergism; D020440:Gene Duplication / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D000077157:Sorafenib; D013234:Stem Cells / Q000166:cytology; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000075746:Zinc Finger Protein Gli2; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C082593:GLI2 protein, human; D053823:Hedgehog Proteins; C541444:IPI-926; D051741:Kruppel-Like Transcription Factors; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D043562:Receptors, G-Protein-Coupled; D050799:STAT5 Transcription Factor; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000075746:Zinc Finger Protein Gli2; D009536:Niacinamide; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3