C3G Regulates Disease Progression and BCR::ABL1 Signaling in Chronic Myeloid Leukemia
Pablo Berrocal Navarro
CIC - Lab. 17
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 fusion oncogene. C3G (encoded by RAPGEF1 gene) is a guanine nucleotide exchange factor (GEF) for Rap1 and R-Ras GTPases that interacts with BCR::ABL1, forming signaling complexes involved in adhesion and cytoskeletal regulation. Both the full-length and truncated (p87C3G) isoforms are expressed in CML cells, with the p87 isoform being overexpressed, suggesting a potential role for C3G in disease development and progression.
To investigate this, we combined a p210-BCR::ABL1 transgenic mouse model that recapitulates key features of chronic-phase CML with conditional Rapgef1 deletion in hematopoietic stem and progenitor cells, alongside Ba/F3 p210 cell lines engineered to overexpress or silence C3G.
C3G deficiency in mice resulted in attenuated disease progression, characterized by reduced granulocyte expansion, delayed onset, and prolonged survival—particularly in females. Alterations in bone marrow progenitor populations and impaired neutrophil maturation and mobilization likely contributed to this phenotype. In parallel, modulation of C3G expression levels in Ba/F3 p210 cells increased sensitivity to imatinib and disrupted phosphorylation of BCR::ABL1 and STAT3/5, indicating perturbations in key leukemogenic signaling pathways.
Together, these findings identify C3G as a regulator of BCR::ABL1 signaling and CML progression. Its loss mitigates disease severity, highlighting C3G as a potential therapeutic target and modulator of leukemogenic signaling in CML.