ArticleMolecular cancer2022
Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia.
Article in Molecular cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 49 citations in OpenAlex.
- Article
- RRAS and RRAS2 Mutations Are Recurrent Oncogenic Drivers in Lung Cancer and Are Sensitive to the Pan-RAS Inhibitor RMC-6236.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- The role of inflammation in the immune evasion of KRas.Frontiers in immunology · 2026Review
- The Hippo-YAP signaling pathway promotes hepatocellular carcinoma progression by inducing FHL3 expression.Cell death & disease · 2025Article
- Ras-related protein 2 limits vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development.Nature communications · 2025Article
- Identification and immune characteristics of N6-methyladenosine related ferroptosis-related genes in intervertebral disc degeneration.Scientific reports · 2025Article
- Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking RAS proteins.Oncogene · 2025Article
- The R-RAS2 GTPase is a signaling hub in triple-negative breast cancer cell metabolism and metastatic behavior.Journal of hematology & oncology · 2025Article
- Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation.Nature communications · 2025Article
- Unmutated RRAS2 emerges as a key oncogene in post-partum-associated triple negative breast cancer.Molecular cancer · 2024Article
- Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.Zoological research · 2024Article
- The ancestral type of the R-RAS protein has oncogenic potential.Cellular & molecular biology letters · 2024Article
- Application and research progress of single cell sequencing technology in leukemia.Frontiers in oncology · 2024Review
- Mice Overexpressing Wild-TypeCancers · 2023Article
- Article
- Early-Life Exposure to Lipopolysaccharide Induces Persistent Changes in Gene Expression Profiles in the Liver and Spleen of Female FVB/N Mice.Veterinary sciences · 2023Article
- SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1.Biomarker research · 2023Article
- PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma.The Journal of investigative dermatology · 2023Article
- Article
- The oncogenic potential of Rab-like protein 1A (RBEL1A) GTPase: The first review of RBEL1A research with future research directions and challenges.Journal of Cancer · 2023Review
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundChronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL.
methodsConditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3'UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL.
resultsRRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3'UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL.
conclusionsThe results indicate that overexpression of wild type RRAS2 is behind the development of CLL.
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