Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

Resumen

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world. Although it is well known that autonomous B cell receptor (BCR) signaling is involved and that mutations in specific genes are associated with worse disease prognosis, no specific driver for this cancer has been identified so far. One family of genes that is known to mediate tumorigenesis upon mutation is the classical RAS protein genes (KRAS, HRAS and NRAS). In this thesis project we have used knock-in mouse models that overexpress the RAS-related protein gene RRAS2 both ubiquitously and in a B cell specific manner. Parallel to this, we have analyzed blood samples from more than 200 untreated human B-CLL patients. As a result of this research, we have demonstrated and published last year (Hortal et al., 2022) that RRAS2 is a driver of B-CLL development. Additionally, in this paper we have also shown that a SNP in the 3’UTR of RRAS2, rs8570, is associated to multiple parameters of worse disease prognosis in untreated B-CLL patients. Additionally, we have further characterized our Rosa26-RRAS2fl/flxmb1-Cre mouse model and we have demonstrated with ibrutinib and venetoclax treatments that it can be used as a tool to test new therapeutic strategies for B-CLL. Analysis of a cohort of 27 ibrutinib-treated patients has demonstrated that, unlike in the case of untreated patients, the presence of at least a C nucleotide at the SNP position rs8570 is associated to a significantly improved response to ibrutinib therapy, as we also published earlier this year (Hortal et al., 2023). In conclusion, the results of this thesis project have demonstrated that RRAS2 is a driver for B-CLL development, making it an attractive target for novel targeted therapeutic strategies. Additionally, the analysis of the rs8570 SNP has revealed it to be an easy to characterize tool. If the results obtained in ibrutinib-treated patients are confirmed in a larger cohort and, ideally, with other treatment options, this approach can help direct current therapeutic strategies towards an optimized patient outcome