Age-Specific Induction of Mutant P53 Drives Clonal Hematopoiesis and Acute Myeloid Leukemia in Adult Mice

Authors

Rasoul Pourebrahim
Rafael Heinz Montoya
Hiroki Akiyama
Lauren Ostermann
Shayuan Khazaei
Muharrem Muftuoglu
Natalia Baran
Ran Zhao
Tom Lesluyes
Bin Liu
Joseph D Khoury
Mihai Gagea
Peter Van Loo
Michael Andreeff

Publication Date

5-21-2024

Journal

Cell Reports Medicine

Abstract

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

Keywords

Animals, Tumor Suppressor Protein p53, Leukemia, Myeloid, Acute, Clonal Hematopoiesis, Mice, Mutation, Proto-Oncogene Proteins c-mdm2, Hematopoietic Stem Cells, Mice, Inbred C57BL, Haploinsufficiency, Disease Models, Animal, Hematopoiesis

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Supplementary Materials

PMID: 38733986