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

Autor: Jalnapurkar SS; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Pawar AS; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Biomedical Graduate Studies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., George SS; Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Antony C; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Somers P; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Grana J; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Feist VK; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Gurbuxani S; Department of Pathology, University of Chicago, Chicago, IL, USA., Paralkar VR; Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. vikram.paralkar@pennmedicine.upenn.edu.; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. vikram.paralkar@pennmedicine.upenn.edu.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. vikram.paralkar@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Sep; Vol. 38 (9), pp. 1938-1948. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1038/s41375-024-02340-5
Abstrakt: Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated 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 expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. 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. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.
(© 2024. The Author(s).)
Databáze: MEDLINE
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