Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice.

Mdm2 haploinsufficiency TP53 mutations acute myeloid leukemia cholesterol biosynthesis clonal hematopoiesis hematopoietic stem cells mevalonate pathway mouse model myeloid-biased hematopoiesis

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
06 May 2024
Historique:
received: 16 08 2023
revised: 18 02 2024
accepted: 17 04 2024
medline: 12 5 2024
pubmed: 12 5 2024
entrez: 11 5 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2024.101558 PMID: 38733986
pubmed: 38733986
pii: S2666-3791(24)00250-7
doi: 10.1016/j.xcrm.2024.101558
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101558

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no potential conflicts of interest.

Auteurs

Rasoul Pourebrahim (R)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Rafael Heinz Montoya (RH)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hiroki Akiyama (H)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Lauren Ostermann (L)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Shayuan Khazaei (S)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Muharrem Muftuoglu (M)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Natalia Baran (N)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ran Zhao (R)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Tom Lesluyes (T)

Cancer Genomics Laboratory, The Francis Crick Institute, London, UK.

Bin Liu (B)

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Joseph D Khoury (JD)

Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, USA.

Mihai Gagea (M)

Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Peter Van Loo (P)

Cancer Genomics Laboratory, The Francis Crick Institute, London, UK; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Michael Andreeff (M)

Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mandreef@mdanderson.org.

Classifications MeSH