RHOA controls oncogenic B cell receptor signaling in aggressive lymphoma
Abstract
Diffuse large B cell lymphoma (DLBCL) is characterized by a variety of specific genetic alterations that impact signaling pathway dependencies and therapeutic outcomes. Among the recurrently mutated genes, we identified RHOA , a member of the small GTPase family, as a selective dependency in DLBCL. Here, we show that RHOA function is essential for the survival of ABC DLBCL cells because it sustains oncogenic B cell receptor (BCR) signaling through maintaining a signaling-permissive conformation of the cortical actin network. This enables the formation of active BCR microclusters at the cell surface, ultimately resulting in constitutive, BCR-driven NF-κB survival signaling. Moreover, we found that RHOA controlled endocytosis of the BCR and thereby the assembly of the endolysosomal My–T–BCR multiprotein complex, a central activator of NF-κB consisting of MYD88, Toll-like receptor 9, and the internalized BCR. The recurrent DLBCL-associated RHOA R5W mutation rendered RHOA constitutively active in its GTP-bound state and changed the conformation of the actin network from primarily filamentous actin to globular actin. This altered actin state led to an increase in BCR microcluster formation, amplification of NF-κB signaling, and resistance to inhibitors targeting chronic active BCR signaling. Hence, our study establishes RHOA and its mutant isoforms as critical regulators of oncogenic BCR signaling in DLBCL.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Ariana N. Jacobs
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Dominique Jahn
Frankfurt Cancer Institute, Goethe University Frankfurt
Tim Beringer
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Sebastian Wolf
Ramesh K. Krishnan
Frankfurt Cancer Institute, Goethe University Frankfurt
Michael Engelke
Institute for Cellular and Molecular Immunology, University Medical Center Göttingen
Björn Häupl
Frankfurt Cancer Institute, Goethe University Frankfurt
Silvia Münch
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Niklas Dienstbier
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Martine Pape
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Marion Bodach
Frankfurt Cancer Institute, Goethe University Frankfurt
Xin Yu
BGI Research, Qingdao, China.
Nazli Serin
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Rebecca Wurm-Kuczera
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Alena Zindel
Frankfurt Cancer Institute, Goethe University Frankfurt
Carmen Döbele
Frankfurt Cancer Institute, Goethe University Frankfurt
Björn Chapuy
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Louis M. Staudt
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health
Sebastian Scheich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Thomas Oellerich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University