Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors

Antonis Dagklis, Sofie Demeyer, Jolien De Bie, Enrico Radaelli, Daphnie Pauwels, Sandrine Degryse, Olga Gielen, Carmen Vicente, Roel Vandepoel, Ellen Geerdens, Anne Uyttebroeck, Nancy Boeckx, Charles E. de Bock and Jan Cools

Key Points

  • A subset of T-ALL cases show high expression of hedgehog pathway genes including the SHH ligand and the GLI1 transcription factor.

  • T-ALL samples with high GLI1 expression levels respond to hedgehog inhibitor treatment in vitro and in vivo.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood leukemia that is caused by the accumulation of multiple genomic lesions resulting in transcriptional deregulation and increased cell proliferation and survival. Through analysis of gene expression data, we provide evidence that the hedgehog pathway is activated in 20% of T-ALL samples. Hedgehog pathway activation is associated with ectopic expression of the hedgehog ligands Sonic hedgehog (SHH) or Indian hedgehog (IHH), and with upregulation of the transcription factor GLI1. Ectopic expression of SHH or IHH in mouse T cells in vivo caused hedgehog pathway activation in both lymphoid and epithelial cells in the thymus and resulted in increased expression of important T-cell stimulatory ligands (Dll4, Il7, and Vegf) by thymic epithelial cells. In T-ALL cell lines, pharmacological inhibition or short interfering RNA–mediated knockdown of SMO or GLI1 led to decreased cell proliferation. Moreover, primary T-ALL cases with high GLI1 messenger RNA levels, but not those with low or undetectable GLI1 expression, were sensitive to hedgehog pathway inhibition by GANT61 or GDC-0449 (vismodegib) using ex vivo cultures and in vivo xenograft models. We identify the hedgehog pathway as a novel therapeutic target in T-ALL and demonstrate that hedgehog inhibitors approved by the US Food and Drug Administration could be used for the treatment of this rare leukemia.

  • Submitted March 4, 2016.
  • Accepted September 18, 2016.
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