Extracellular cyclophilin A promotes B-cell acute lymphoblastic leukemia progression via MC2R.

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by rapid proliferation of immature lymphoid cells. Despite treatment advancements, relapse remains a significant challenge. Understanding the molecular mechanisms that drive B-ALL progression is essential for developing more effective treatments. Here, we show that extracellular cyclophilin A (eCypA) is elevated in patients with B-ALL via both autocrine and paracrine mechanisms. Moreover, eCypA administration exacerbated B-ALL progression in a mouse model. Mechanistically, eCypA binds to the melanocortin 2 receptor and activates the downstream cAMP-PKA-CREB signaling pathway. This activation upregulates CD44, FN1, and MMP9 to promote trans-endothelial migration of B-ALL cells and increases the expression of anti-apoptotic proteins, thereby inhibiting cell apoptosis. Antibodies against CypA modestly reduced leukemia burden and delayed disease progression in both NALM6 xenograft and patient-derived xenograft mouse models. Furthermore, single-cell transcriptomics suggests that anti-CypA treatment reduces the proportion of cells with multipotent progenitor features and is accompanied by decreased CREB pathway activation. Collectively, these findings indicate that eCypA contributes to the progression of B-ALL and may represent a potential therapeutic target.