Format

Send to

Choose Destination
Leukemia. 2018 Oct;32(10):2126-2137. doi: 10.1038/s41375-018-0097-x. Epub 2018 Mar 20.

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

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
4
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
5
Division of Oncology and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
6
Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94158, USA.
7
Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
8
Division of Oncology, University of Virginia Children's Hospital, Charlottesville, VA, 22903, USA.
9
Department of Laboratory Medicine, University of Washington, Seattle, 98195, WA, USA.
10
Department of Biostatistics, University of Florida, Gainesville, FL, 32611, USA.
11
Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA.
12
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA. alejandro.gutierrez@childrens.harvard.edu.
13
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. alejandro.gutierrez@childrens.harvard.edu.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center