NG2-ITGA4 axis regulates Rho GTPases and leukemic aggressiveness in KMT2A-r B-ALL and is targetable with natalizumab
Abstract
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 (R/R) disease, relapses remain common and long-term survival is especially poor in KMT2A-r B-ALL patients. We recently identified the membrane-bound proteoglycan NG2 (CSPG4) as 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) - an FDA/EMA-approved monoclonal antibody targeting ITGA4 - delayed leukemia progression and potentiated the efficacy of standard-of-care chemotherapy in KMT2A-r B-ALL patient-derived xenograft (PDX) 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.
Article Details
Authors (25)
Alba Rubio-Gayarre
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Meritxell Vinyoles
Juan Ramón Tejedor
Institute of Oncology of Asturias (IUOPA), ISPA-HUCA, Spain
Mercedes Guerrero-Murillo
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Narcís Fernandez-Fuentes
Josep Carreras Leukemia Research Institute., Barcelona, Spain
Rita Caracuel-Peramos
GENYO. Center for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain
Maria Carmen Plaza-Calonge
GENYO. Center for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain
Alba Martinez-Moreno
Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine,, Barcelona, Spain
Heleia Roca-Ho
IJC, Barcelona, Spain
Paolo Petazzi
Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Alba Pañella-Alférez
GENYO. Center for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain
Angela Meseguer-Giron
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Kirsten S. Vrenken
Princess Maxima Center, Utrecht, Netherlands
Mario F Fraga
CINN-ISPA, Oviedo, Spain
Pilar Leoz Allegretti
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Carlos Palacio-Garcia
4. Servei d'Hematologia, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain, Barcelona, Spain
Pablo Velasco
Hospital Vall d'Hebrón. Universitat Autonoma de Barcelona, Barcelona, Spain
José Luis Fuster
Hospital Clínico Universitario Virgen de la Arrixaca. Instituto Murciano de Investigación Biosanitaria (IMIB), Pilar de la Horadada. Alicante, Spain
Ronald W. Stam
Juan Carlos Rodríguez-Manzaneque
GENYO. Center for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain
Xose R Bustelo
Centro de Investigacion del Cancer, Salamanca, Spain
Javier Robles-Valero
Centro de Investigacion del Cancer, Salamanca, Spain
Pablo Menendez
Clara Bueno
Josep Carreras Leukemia Research Institute, Barcelona, Spain
Belén Lopez-Millan
Josep Carreras Leukemia Research Institute, Barcelona, Spain