Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies.
In: Cancers, Jg. 15 (2023-12-15), Heft 24, S. 5817-5833
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Simple Summary: Chronic lymphocytic leukemia (CLL) is a prevalent blood cancer, more common in men in their sixties or older. Unlike some other cancers linked to the KRAS gene, CLL is associated with a gene called RRAS2, which is overly active but not mutated. In a significant discovery, we established a mouse model by increasing RRAS2 levels, resulting in CLL development in 100% of cases. This model is essential for testing potential treatments before human trials. In this study, we validated the mouse model by evaluating two widely used CLL drugs, ibrutinib and venetoclax, and found that they effectively killed leukemia cells in the mice. This validation indicates that the mouse model can reliably simulate CLL responses to established drugs. Importantly, it opens the door to testing novel drugs, including those targeting RRAS2, which has not been explored in clinical settings. This advancement is a crucial step toward identifying improved therapies for CLL and holds promise for future developments in leukemia treatment. B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2 fl/fl xmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic. [ABSTRACT FROM AUTHOR]
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Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies.
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Autor/in / Beteiligte Person: | Hortal, Alejandro M. ; Villanueva, Ana ; Arellano, Irene ; Prieto, Cristina ; Mendoza, Pilar ; Bustelo, Xosé R. ; Alarcón, Balbino |
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Zeitschrift: | Cancers, Jg. 15 (2023-12-15), Heft 24, S. 5817-5833 |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 2072-6694 (print) |
DOI: | 10.3390/cancers15245817 |
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