<i>Phf6</i> Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL

Abstract

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