PUBLICATION

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

Authors
Burns, M.A., Liao, Z.W., Yamagata, N., Pouliot, G.P., Stevenson, K.E., Neuberg, D.S., Thorner, A.R., Ducar, M., Silverman, E.A., Hunger, S.P., Loh, M.L., Winter, S.S., Dunsmore, K.P., Wood, B., Devidas, M., Harris, M.H., Silverman, L.B., Sallan, S.E., Gutierrez, A.
ID
ZDB-PUB-180418-39
Date
2018
Source
Leukemia   32(10): 2126-2137 (Journal)
Registered Authors
Gutierrez, Alejandro
Keywords
none
MeSH Terms
  • 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
PubMed
29654263 Full text @ 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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes