Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors.
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.
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Antonis
A
Dagklis
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Sofie
S
Demeyer
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Jolien
J
De Bie
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Enrico
E
Radaelli
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Daphnie
D
Pauwels
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Sandrine
S
Degryse
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Olga
O
Gielen
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Carmen
C
Vicente
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Roel
R
Vandepoel
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Ellen
E
Geerdens
Pediatric Oncology and.
Anne
A
Uyttebroeck
Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium; and.|Department of Oncology, KU Leuven, Leuven, Belgium.
Nancy
N
Boeckx
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Charles E
CE
de Bock
KU Leuven Center for Human Genetics, Leuven, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
Jan
J
Cools
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000813:Anilides; C551027:GANT 61; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D009363:Neoplasm Proteins; D011725:Pyridines; D011743:Pyrimidines; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1