Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All

Agnieszka A. Wendorff, S. Aidan Quinn, Marissa Rashkovan, Chioma J. Madubata, Alberto Ambesi-Impiombato, Mark R. Litzow, Martin S. Tallman, Elisabeth Paietta, Maddalena Paganin, Giuseppe Basso, Julie M. Gastier-Foster, Mignon L. Loh, Raul Rabadan, Pieter Van Vlierberghe, Adolfo A. Ferrando

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)436-451
Number of pages16
JournalCancer discovery
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Oncology

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    Wendorff, A. A., Quinn, S. A., Rashkovan, M., Madubata, C. J., Ambesi-Impiombato, A., Litzow, M. R., Tallman, M. S., Paietta, E., Paganin, M., Basso, G., Gastier-Foster, J. M., Loh, M. L., Rabadan, R., Vlierberghe, P. V., & Ferrando, A. A. (2019). Phf6 loss enhances HSC self-renewal driving tumor initiation and leukemia stem cell activity in T-All. Cancer discovery, 9(3), 436-451. https://doi.org/10.1158/2159-8290.CD-18-1005