Detalle Publicación

Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI inhibitors
Autores: Dagklis, A.; Demeyer, S.; De Bie, J.; Radaelli, E.; Pauwels, D.; Degryse, S.; Gielen, O.; Vicente Vázquez, Carmen; Vandepoel, R.; Geerdens, E.; Uyttebroeck, A.; Boeckx, N.; De Bock Charles E.; Cools, Jan
Título de la revista: BLOOD
ISSN: 0006-4971
Volumen: 128
Número: 23
Páginas: 2642 - 2654
Fecha de publicación: 2016
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 SHH or 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, Vegf) by thymic epithelial cells. In T-ALL cell lines, pharmacological inhibition or siRNA mediated knock-down of SMO or GLI1 led to decreased cell proliferation. Moreover, primary T-ALL cases with high GLI1 mRNA 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 FDA approved hedgehog inhibitors could be used for the treatment of this rare leukemia.