Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

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.

• 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
• Journal: Leukemia (Leukemia) Vol. 32 Issue 10 Pg. 2126-2137 (10 2018) ISSN: 1476-5551 [Electronic] England
• PMID: 29654263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hedgehog Proteins

Topics

• Adolescent
• Animals
• Carcinogenesis (genetics)
• Cell Transformation, Neoplastic (genetics)
• Child
• Child, Preschool
• Female
• Hedgehog Proteins (genetics)
• Humans
• Male
• Mutation (genetics)
• Oncogenes (genetics)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics)
• Signal Transduction (genetics)
• T-Lymphocytes (physiology)
• Zebrafish