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Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity

Oncogene (2018) | Download Citation


Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

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We would like to acknowledge Dr. David Huso, previously an Associate Professor in the Department of Molecular and Comparative Pathobiology at Johns Hopkins, for preparing the histology slides; and Dr. Hao Zhang, Research Associate in the Department of Molecular Microbiology and Immunology at Johns Hopkins, for helping to sort the murine bone marrow for cell subpopulations. This work was supported by grants from the National Institute of Health (K08 HL136894) (LPG) and Edward P. Evans Foundation (LPG). Flow cytometry and microarray analysis was performed with the support of the Sidney Kimmel Comprehensive Cancer Center Core Facilities (P30 CA006973).

Author information


  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    • Bonnie W. Lau
    • , Kyounghee Huh
    • , Rafael Madero-Marroquin
    • , Federico De Marchi
    • , Yiting Lim
    • , Qiuju Wang
    • , Francisco Lobo
    • , Luigi Marchionni
    • , Douglas B. Smith
    • , Amy DeZern
    • , Mark J. Levis
    •  & Lukasz P. Gondek
  2. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    • Yiting Lim
  3. Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    • Francisco Lobo
  4. Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    • Peter D. Aplan
  5. LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712USA, USA

    • William Matsui


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The authors declare that they have no conflict of interest.

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Correspondence to William Matsui or Lukasz P. Gondek.

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