T-ALL can evolve to oncogene independence.

Autor: Abdulla H; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Vo A; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Shields BJ; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Davies TJ; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Jackson JT; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Alserihi R; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; College of Applied Medical Sciences, King Abdul-Aziz University, Jeddah, Saudi Arabia., Viney EM; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Wong T; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Yan F; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.; Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia., Wong NC; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.; Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia., Demoen L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Curtis DJ; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Alexander WS; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Van Vlierberghe P; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Dickins RA; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., McCormack MP; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia. matthew.mccormack@monash.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2021 Aug; Vol. 35 (8), pp. 2205-2219. Date of Electronic Publication: 2021 Jan 22.
DOI: 10.1038/s41375-021-01120-9
Abstrakt: The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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