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bioRxiv · 10.1101/2024.01.06.573649

PHF6 suppresses self-renewal of leukemic stem cells in AML

Jalnapurkar, S. S.·Pawar, A.·George, S. S.·Antony, C.·Grana, J.·Gurubuxani, S.·Paralkar, V. R.
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Abstract

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 Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the LIC-e (leukemia initiating cells enriched) population. We find that Phf6 loss has context-specific transcriptional effects, skewing the LIC-e transcriptome to a more stem-like state. We demonstrate that LIC-e accumulation in Phf6 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 Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells. Statement of SignificanceLeukemia stem cell self-renewal is critical to the pathophysiology of AML. Phf6 deletion accelerates mouse AML by increasing LSC self-renewal, specifically by increasing the fraction of LSC progeny that retain LSC identity. Our work shows how a repressor of HSC self-renewal is inactivated in AML to drive LSC stemness.

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Jalnapurkar, S. S., Pawar, A., George, S. S., Antony, C., Grana, J., Gurubuxani, S., Paralkar, V. R.. 2024-01-07. PHF6 suppresses self-renewal of leukemic stem cells in AML. https://doi.org/10.1101/2024.01.06.573649

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