PHF6 suppresses self-renewal of leukemic stem cells in AML.

Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its loss increases mouse HSC self-renewal without malignant transformation. We report here that knockout increases the aggressiveness of -driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the hierarchy of -driven AML and identify a population that we term the 'LIC-e' (leukemia initiating cells enriched) population. We find that loss has context-specific transcriptional effects, skewing the LIC-e transcriptome to a more stem-like state. We demonstrate that LIC-e accumulation in knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Overall, our work indicates that loss increases AML self-renewal through context-specific effects on leukemia stem cells.