Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy
Year: 2026
Type: article
Abstract: Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target. Monoallelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of GPRC5D to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic GPRC5D loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D alters the transcriptional state of MM cells and promotes reprogramming of the phosphoproteomic circuitry ultimately resulting in a pro-proliferative chemokine environment. As a result, GPRC5D deficiency increases the basal proliferation rate of MM cells thereby providing a competitive advantage which may further be amplified by selecting these aggressive phenotypes during ongoing treatment with anti-GPRC5D immunotherapies.
Source: Leukemia
Authors: Umair Munawar, Johanna Thurner, Silvia Nerreter, Thomas Nerreter, Alexander M. Leipold, Seungbin Han, Christina Verbruggen, Elena Gerhard-Hartmann, Cornelia Vogt, Björn Grams, Shilpa Kurian, Emma Besant, Sabine Roth, Julia Weingart, Patrick Eiring, Marietta Truger, Nazia Afrin, Torsten Steinbrunn, Yoko Tamamushi, Xiang Zhou, Nina Rein, Johanna Lehmann, Max Köppel, Andreas Rosenwald, Claudia Haferlach, Michael Hudecek, Antoine-Emmanuel Saliba, Leo Rasche, Markus Sauer, Hermann Einsele, Bernhard Kuster, Johannes Waldschmidt, K. Martin Kortüm
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
Awards: TRR 338: LETSIMMUN Lymphozyten Engineering für Therapeutische Synthetische Immunität, G2576477382, G2930764506, CRISPRbasierte funktionelle Genomik für Untersuchungen zur Regulation der Zellantwort auf Pertubation der Funktion von mutiertem RAS im Multiplen Myelom: biologische und therapeutische Implikationen., SFB 1583: Entscheidungsprozesse bei Infektionskrankheiten (DECIDE), G478389428, Elucidation of risk factors and health determinants associated with PROGRESSION of Monoclonal Gammopathies to Multiple Myeloma, G7127209473, G7157540364, G782482008, G848503479
OpenAlex ID: W7147533144