CD38 as a therapeutic target in pediatric Burkitt’s Lymphoma: insights from a comparative approach (Running title: Targeting CD38 in pediatric Burkitt's Lymphoma)

Abstract

Abstract Background Pediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin's B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse and resistance to current therapies remains challenging. CD38, a transmembrane protein highly expressed in pBL, is a promising therapeutic target. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab (DARA) and isatuximab (ISA), in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods In silico analyses of pBL cell line and patient sample datasets, combined with in vitro experiments using the Ramos cell line model, were conducted to assess the impact of DARA and ISA on cellular proliferation, apoptosis, and the phosphoinositide 3-kinase (PI3K) pathway. Comparative approaches were utilized to evaluate the therapeutic potential of these mAbs, focusing on B-cell receptor signaling, calcium flux, metabolic shifts, and interaction of key proteins on the cell surface. Results ISA was found to be more effective than DARA in disrupting B-cell receptor signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, ISA caused a significant impairment of the PI3K pathway and induced metabolic shifts in pBL cells, indicating its role in metabolic reprogramming. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38's involvement in key oncogenic processes. Conclusions The study emphasizes the therapeutic potential of CD38-targeting mAbs, particularly ISA, in pBL. These findings suggest that targeting CD38 with mAbs may offer a novel approach for treating pBL, particularly in cases where patients show resistance or relapse after conventional therapies.