Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL
Year: 2018
Type: article
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
Source: Cancer Discovery
Institutions: Columbia University, Columbia University Irving Medical Center, Mayo Clinic, Memorial Sloan Kettering Cancer Center, Albert Einstein College of Medicine, University of Padua, Italian institute for Genomic Medicine, Nationwide Children's Hospital, Children's Oncology Group, The Ohio State University, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Ghent University, Cancer Research Institute Ghent
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1311324608, ECOG-ACRIN Network Group Operations Center, Network Lead Academic Participating Site: Memorial Sloan-Kettering Cancer Center, EASTERN COOPERATIVE ONCOLOGY GROUP, MINORITY-BASED COMMUNITY ONCOLOGY PROGRAM, Molecular pathways and targeted therapies in human leukemia, (PQB5) Reconstruction of Evolutionary Networks using Cross-Sectional Genomic Data, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), Network Lead Academic Participating Site: Memorial Sloan Kettering Cancer Center, Centers for Cancer Systems Therapeutics (CaST), ECOG-ACRIN Integrated Leukemia Translational Science Center (LTSC), ECOG Clinical Trials, Topology of Cancer Evolution and Heterogeneity, The role of PHF6 in T-cell acute lymphoblastic leukemia, Children's Oncology Group Chair's Grant, ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTER, Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine, G9000113362, Cancer Center Support Grant, ECOG-ACRIN Biospecimen Bank to Support NCTN, Cancer Center Support Grant, Cancer Center Support Grant
OpenAlex ID: W2904609036