C3G in chronic myeloid leukemia: linking disease progression in mouse models with cellular leukemogenic mechanisms

Abstract

[EN]Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 fusion oncogene, a constitutively active tyrosine kinase that transforms hematopoietic stem cells (HSCs) and generates leukemic stem cells, which sustain disease progression and treatment resistance. C3G, a regulator of the Rap1 GTPase, interacts with BCR::ABL1 and participates in processes such as cell signaling, adhesion, and differentiation. In addition, C3G plays an active role in hematopoiesis, regulating HSC fate and hematopoietic differentiation. Although its role in CML was previously unclear, this study demonstrates that its regulation is critical.

In a murine model of CML, early deletion of C3G attenuates disease development: it delays onset, reduces circulating neutrophils, decreases leukemic infiltration, and prolongs survival (particularly in females). These effects are associated with alterations in myeloid progenitors—specifically, an accumulation of granulocyte-committed progenitors—and with impaired neutrophil migration and functional capacity. At the cellular level, both overexpression and inhibition of C3G in BCR::ABL1 positive cells do not affect proliferation but do increase sensitivity to imatinib. This enhanced response correlates with reduced activation of the JAK/STAT pathway (JAK2, STAT3, STAT5), while other pathways such as ERK or AKT remain largely unchanged. Moreover, low C3G levels impair STAT3-dependent neutrophil differentiation under non-oncogenic conditions.

Overall, C3G functions as a fine-tuned modulator of leukemogenic signaling, with intermediate levels required for optimal pathway activity. Its dysregulation limits CML progression and enhances treatment response, positioning C3G as a potential therapeutic target to improve the efficacy of tyrosine kinase inhibitors.