Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-10

AUTHORS

Melissa A. Burns, Zi Wei Liao, Natsuko Yamagata, Gayle P. Pouliot, Kristen E. Stevenson, Donna S. Neuberg, Aaron R. Thorner, Matthew Ducar, Emily A. Silverman, Stephen P. Hunger, Mignon L. Loh, Stuart S. Winter, Kimberly P. Dunsmore, Brent Wood, Meenakshi Devidas, Marian H. Harris, Lewis B. Silverman, Stephen E. Sallan, Alejandro Gutierrez

ABSTRACT

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease. More... »

PAGES

2126-2137

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-018-0097-x

DOI

http://dx.doi.org/10.1038/s41375-018-0097-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101628327

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29654263


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