Overexpression of Lmo2 initiates T-lymphoblastic leukemia via impaired thymocyte competition.

Autor:	Abdulla HD; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Alserihi R; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia.; College of Applied Medical Sciences, King Abdul-Aziz University , Jeddah, Saudi Arabia., Flensburg C; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Abeysekera W; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Luo MX; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Gray DHD; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Liu X; Westlake Laboratory of Life Sciences and Biomedicine , Hangzhou, China.; School of Life Sciences, Westlake University , Hangzhou, China.; Westlake Institute for Advanced Study , Hangzhou, China., Smyth GK; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; School of Mathematics and Statistics, University of Melbourne , Parkville, Australia., Alexander WS; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., Majewski IJ; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia., McCormack MP; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, University of Melbourne , Parkville, Australia.; Australian Centre for Blood Diseases, Monash University , Melbourne, Australia.; iCamuno Biotherapeutics, Melbourne , Australia.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2023 Jun 05; Vol. 220 (6). Date of Electronic Publication: 2023 Mar 15.
DOI:	10.1084/jem.20212383
Abstrakt:	Cell competition has recently emerged as an important tumor suppressor mechanism in the thymus that inhibits autonomous thymic maintenance. Here, we show that the oncogenic transcription factor Lmo2 causes autonomous thymic maintenance in transgenic mice by inhibiting early T cell differentiation. This autonomous thymic maintenance results in the development of self-renewing preleukemic stem cells (pre-LSCs) and subsequent leukemogenesis, both of which are profoundly inhibited by restoration of thymic competition or expression of the antiapoptotic factor BCL2. Genomic analyses revealed the presence of Notch1 mutations in pre-LSCs before subsequent loss of tumor suppressors promotes the transition to overt leukemogenesis. These studies demonstrate a critical role for impaired cell competition in the development of pre-LSCs in a transgenic mouse model of T cell acute lymphoblastic leukemia (T-ALL), implying that this process plays a role in the ontogeny of human T-ALL. (© 2023 Abdulla et al.)
Databáze:	MEDLINE
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