Characterization of Three Somatic Mutations in the 3'UTR of RRAS2 and Their Inverse Correlation with Lymphocytosis in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by progressive accumulation of a rare population of CD5+ B-lymphocytes in peripheral blood, bone marrow, and lymphoid tissues. CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3' untranslated region (3'UTR) affecting positions +26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3'UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.

An Optimized Single Nucleotide Polymorphism-Based Detection Method Suggests That Allelic Variants in the 3' Untranslated Region of RRAS2 Correlate with Treatment Response in Chronic Lymphocytic Leukemia Patients.

Unlike classical RAS genes, oncogenic mutations on RRAS2 are seldomly found in human cancer. By contrast, RRAS2 is frequently found overexpressed in a number of human tumors, including B and T cell lymphomas, breast, gastric, head and neck cancers. In this regard, we have recently shown that overexpression of wild-type RRAS2 drives the formation of both chronic lymphocytic leukemia (CLL) and breast cancer in mice. In support for the relevance of overexpression of wild type RRAS2 in human cancer, we have found that RRAS2 expression is influenced by the presence of a specific single nucleotide polymorphism (SNP) located in the 3'-untranslated region (UTR) of the RRAS2 mRNA. Perhaps more importantly, the presence of the alternate C, rather than the G allele, at the RRAS2 SNP designated as rs8570 is also associated with worse patient prognosis in CLL. This indicates that the detection of this SNP allelic variants can be informative to predict RRAS2 expression levels and disease long-term evolution in patients. Here, we describe a polymerase chain reaction (PCR)-based method that facilitates the rapid and easy determination of G and C allelic variants of the SNP. Using this approach, we confirm that the C allelic variant is associated with higher expression levels of RRAS2 transcripts and poor patient prognosis. However, we have also found that expression of the C allelic variants correlates with better response to ibrutinib, a Bruton kinase inhibitor commonly used in CLL treatments. This suggests that this method for detecting the RRAS2 rs8570 SNP might be a useful as a tool to predict both patient prognosis and response to targeted therapy in CLL.