POS0400 MODULATION OF HUMAN EARLY B CELL DEVELOPMENT THROUGH TARGETED DEGRADATION OF IKAROS AND AIOLOS WITH IBERDOMIDE

Abstract

BackgroundB differentiation in the bone marrow (BM) is impaired in patients carrying mutation in the IKFZ1 gene, coding for Ikaros a zinc-finger transcription factor. High Ikaros expression is on the contrary associated with systemic lupus erythematosus[1] and multiple myeloma[2]. Targeted treatment with iberdomide, a cereblon modulator which enhances degradation of Ikaros and Aiolos, is under clinical investigation in multiple myeloma patients and systemic lupus erythematosus. However, consequences of the treatment on human early B cell development remain elusive. Immature B cells develop in the BM from hematopoietic stem cells. An intricate network of transcription factors regulates the maturation process. Ikaros and Aiolos regulate gene expression during B cell development. As reported in mice, Ikaros is essential for the commitment to the lymphoid lineage and later, together with Aiolos, ensures the transition from pre-BII large to pre-BII small cells.ObjectivesInvestigate the effect of iberdomide (CC-220) on human early B cell development simulated in vitro.MethodsWe tested the impact of iberdomide on short term culture of BM-derived lymphocytes and in a unique in vitro modeling of early B cell development starting from cord blood (CB)- CD34+ progenitors [3, 4]. We used multi-dimensional spectra flow cytometry (17-color pan-el) to dissect early B cell subpopulations.ResultsIberdomide treatment led to enhanced degradation of Ikaros and Aiolos in both BM- and CB-derived cultures. Addition of iberdomide early (day 7) to the CB-derived culture impaired the specification to the lymphoid lineage and later also the commitment to the B cell lineage. These observations were confirmed by reduced E2A and PAX5 gene expression, respectively. Treatment with iberdomide on B cell precursors (pro- and pre-B cells, day 28 of culture) on one side it enhanced the proliferation of early progenitors resulting in increased amount of CD10+CD38+ lymphoid-committed cells. On the other side, it resulted in a accumulation of pre-B cells and inefficient development of immature B cells.ConclusionIberdomide impairs the commitment to the lymphoid lineage by enhancing Ikaros’ degrada-tion. When targeting already committed B cells, iberdomide treatment undermines the transition of pre-BII large to pre-BII small cells due to increased Aiolos’ degradation, conse-quently impairing the development of immature B cells. Our data can instruct immunologi-cal monitoring of patients treated with iberdomide, and provide insights in the mechanisms of therapeutic efficacy.References[1]Rivellese, F., et al., Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus. Lupus Sci Med, 2021. 8(1).[2]Thakurta, A., et al., Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Oncotarget, 2021. 12(15): p. 1555-1563.[3]Kraus, H., et al., A Feeder-Free Differentiation System Identifies Autonomously Proliferating B Cell Precursors in Human Bone Marrow. The Journal of Immunology, 2014. 192(3): p. 1044-1054.[4]Troilo, A., et al., Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency. Blood, 2020. 135(17): p. 1452-1457.Disclosure of InterestsIga Janowska: None declared, Jakov Korzhenevich: None declared, Julian Staniek: None declared, Raquel Lorenzetti: None declared, Lukas Konstantinidis: None declared, Miriam Erlacher: None declared, Peter Schafer Employee of: BMS, Reinhard Voll: None declared, Jens Thiel Grant/research support from: BMS (former Cellgene), Nils Venhoff: None declared, Marta Rizzi Grant/research support from: BMS (former Cellgene)