The NG2-ITGA4 axis regulates Rho GTPases and leukemic aggressiveness in KMT2A-r B-ALL and is targetable with natalizumab

KMT2A-rearranged B-cell acute lymphoblastic leukemia (KMT2A-r B-ALL) is an aggressive subtype of leukemia, characterized by high relapse rates, therapy resistance, and poor prognosis. Although CD19-targeted immunotherapies have significantly benefited patients with relapsed/refractory disease, relapses remain common and long-term survival is especially poor in patients with KMT2A-r B-ALL. We recently identified the membrane-bound proteoglycan, neuron-glial antigen 2 (NG2; CSPG4), as a direct transcriptional target of KMT2A fusions, with its expression associated with poor prognosis, early relapse, and glucocorticoid resistance in KMT2A-r B-ALL. However, the molecular mechanism underlying the aggressiveness of KMT2A-r B-ALL remains poorly understood. Here, we identify the α4 integrin subunit (ITGA4) and NG2 as a key biological axis contributing to leukemic aggressiveness. NG2 expression promotes proliferation and migration of KMT2A-r B-ALL cells, and it is associated with Rho GTPase activity in an ITGA4-dependent manner. In vivo studies using immunodeficient mice demonstrated that ITGA4 and NG2 cooperate to promote leukemia progression, as combined genetic ablation of both genes significantly delayed disease onset and prolonged survival. Notably, natalizumab (NTZ), a clinically approved monoclonal antibody targeting ITGA4, delayed leukemia progression and potentiated the efficacy of standard-of-care chemotherapy in patient-derived KMT2A-r B-ALL xenograft models. Collectively, our findings define a novel ITGA4-NG2 signaling axis that drives the aggressiveness of KMT2A-r B-ALL and support the repurpose of NTZ as an adjuvant therapeutic strategy for this high-risk leukemia subtype.