B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such asTP53andATM, 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 GTPaseRRAS2in 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-RRAS2fl/flxmb1-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.
B细胞慢性淋巴细胞白血病（B-CLL）是西方世界最常见的白血病类型。研究表明，TP53和ATM等基因突变以及11q或17p等特定染色体区域缺失与较差的疾病预后相关。我们团队近期研究发现，与通常通过错义突变导致癌症发展的过程不同，B-CLL是由野生型小GTP酶RRAS2的过表达驱动，且未发生激活突变。目前已有若干该疾病的小鼠模型被开发并广泛应用于B-CLL研究，但这些模型存在不同缺陷，例如白血病完全形成所需等待周期较长、需要进行细胞移植，或在某些情况下无法重现人类患者的病理改变。我们近期报道的Rosa26-RRAS2fl/flxmb1-Cre小鼠模型是一种具有完全外显率的新型B-CLL小鼠模型。本研究通过测试两种最广泛应用的靶向药物——伊布替尼和维奈托克，验证了该小鼠模型可作为开发B-CLL新疗法的重要工具。这同时也为针对R-RAS2本身的新型靶向药物研发开辟了道路，该策略目前在临床治疗中尚未得到探索。
肿瘤(癌症)患者之家