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Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia


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.

Type Journal
ISBN 1946-6242 (Electronic) 1946-6234 (Linking)
Authors Lim, Y.; Gondek, L.; Li, L.; Wang, Q.; Ma, H.; Chang, E.; Huso, D. L.; Foerster, S.; Marchionni, L.; McGovern, K.; Watkins, D. N.; Peacock, C. D.; Levis, M.; Smith, B. D.; Merchant, A. A.; Small, D.; Matsui, W.;
Publisher Name Science Translational Medicine
Published Date 2015-01-01
Published Volume 7
Published Issue 291
Published Pages 291ra96
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version