MYB insufficiency disrupts proteostasis in hematopoietic stem cells, leading to age-related neoplasia.

Autor:	Clarke ML; Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Lemma RB; Department of Biosciences, University of Oslo, Oslo, Norway.; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway., Walton DS; Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Volpe G; Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Noyvert B; Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.; CRUK Birmingham Centre and Centre for Computational Biology, University of Birmingham, Birmingham, United Kingdom., Gabrielsen OS; Department of Biosciences, University of Oslo, Oslo, Norway., Frampton J; Institute of Cancer & Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Apr 13; Vol. 141 (15), pp. 1858-1870.
DOI:	10.1182/blood.2022019138
Abstrakt:	MYB plays a key role in gene regulation throughout the hematopoietic hierarchy and is critical for the maintenance of normal hematopoietic stem cells (HSC). Acquired genetic dysregulation of MYB is involved in the etiology of a number of leukemias, although inherited noncoding variants of the MYB gene are a susceptibility factor for many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially concerning age dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads to MPN, myelodysplasia, and leukemia in later life, mirroring the age profile of equivalent human diseases. We show that this age dependency is intrinsic to HSC, involving a combination of an initial defective cellular state resulting from small effects on the expression of multiple genes and a progressive accumulation of further subtle changes. Similar to previous studies showing the importance of proteostasis in HSC maintenance, we observed altered proteasomal activity and elevated proliferation indicators, followed by elevated ribosome activity in young Myb-insufficient mice. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu