Targeting hedgehog in hematologic malignancy
Open Access
- 8 March 2012
- journal article
- review article
- Published by American Society of Hematology in Blood
- Vol. 119 (10), 2196-2204
- https://doi.org/10.1182/blood-2011-10-383752
Abstract
The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.Keywords
This publication has 94 references indexed in Scilit:
- Self-Renewal of Leukemia Stem Cells in Friend Virus-Induced Erythroleukemia Requires Proviral Insertional Activation of Spi1 and Hedgehog Signaling but Not Mutation of p53The International Journal of Cell Cloning, 2012
- Glioma-associated oncogene homologue 3, a hedgehog transcription factor, is highly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphomaHuman Pathology, 2011
- Hedgehog Signaling Is Dispensable for Adult Murine Hematopoietic Stem Cell Function and HematopoiesisCell Stem Cell, 2009
- Hedgehog Signaling Is Dispensable for Adult Hematopoietic Stem Cell FunctionCell Stem Cell, 2009
- Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse developmentDevelopmental Biology, 2009
- In Childhood Acute Lymphoblastic Leukemia, Blasts at Different Stages of Immunophenotypic Maturation Have Stem Cell PropertiesCancer Cell, 2008
- The Gli code: an information nexus regulating cell fate, stemness and cancerTrends in Cell Biology, 2007
- Vertebrate Smoothened functions at the primary ciliumNature, 2005
- Mutations in the human Sonic Hedgehog gene cause holoprosencephalyNature Genetics, 1996
- Mutations affecting segment number and polarity in DrosophilaNature, 1980