Format

Send to

Choose Destination
Cancer Discov. 2019 Mar;9(3):436-451. doi: 10.1158/2159-8290.CD-18-1005. Epub 2018 Dec 19.

Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York.
2
Department of Pediatrics, Columbia University Medical Center, New York, New York.
3
Department of Systems Biology, Columbia University, New York, New York.
4
Division of Hematology, Mayo Clinic, Rochester, Minnesota.
5
Department of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
7
Onco-Hematology Division, Department, Salute della Donna e del Bambino (SDB), University of Padua, Padua, Italy.
8
Italian Institute for Genomic Medicine (HMG), Turin, Italy.
9
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
10
Department of Pathology, Ohio State University School of Medicine, Columbus, Ohio.
11
Department of Pediatrics, Ohio State University School of Medicine, Columbus, Ohio.
12
Children's Oncology Group, Arcadia, California.
13
Department of Pediatrics, University of California, San Francisco, California.
14
Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
15
Department of Biomedical Informatics, Columbia University, New York, New York.
16
Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
17
Cancer Research Institute Ghent, Ghent, Belgium.
18
Institute for Cancer Genetics, Columbia University, New York, New York. af2196@columbia.edu.
19
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.

Abstract

The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL. SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL.This article is highlighted in the In This Issue feature, p. 305.

PMID:
30567843
PMCID:
PMC6425751
[Available on 2020-03-01]
DOI:
10.1158/2159-8290.CD-18-1005

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center