Abstract LB049: ALKBH5 emerges as a novel regulator of the BCR pathway

Abstract

Abstract Global epitranscriptomic methylation of mRNA at the N6 position (m6A) is reported to be altered in B-cell and tumor development. However, the mechanistic underpinnings of its role in the pathogenesis of Diffuse large B cell lymphoma (DLBCL) are unknown. It is well established that the B-cell receptor (BCR) pathway is a primary oncogenic driver in aggressive B-cell lymphomas. We previously reported that the Ataxia Telangiectasia Mutated (ATM)/Hu Antigen R (HuR)axis, as well as Eukaryotic Translation Initiation Factor 4A (eIF4A), modulate BCR signaling. However, the impact of RNA modifications on BCR induction is still poorly understood. Addressing this burgeoning question, we noted enhanced expression of AlkB Homolog 5 (ALKBH5), an m6A demethylase, in naïve B-cells treated with BCR mimetics. Similarly, mRNA levels of ALKBH5 were reported to be modestly enhanced in IgM-treated human B-cells (GSE156195). Consistently, immunization of C57BL/6 mice with sheep red blood cells (SRBC) significantly enhanced ALKBH5 in splenic B-cells. Next, evaluating the impact of BCR induction in lymphomagenesis, we observed a robust increase in the demethylase expression in BCR mimetic-treated DLBCL cells. Notably, increased expression of ALKBH5 was observed in a murine EµMyc model and primary DLBCL tumors. In coherence, the enhanced transcript levels of ALKBH5 in TCGA-DLBCL have prognostic implications. To gain functional insight, we depleted ALKBH5, which resulted in a robust reduction of BCR pathway proteins. Unexpectedly, the mRNA levels of CD79a and BLK were minimally modified, while the SYK, BTK, and CARD11 messages were reduced. Further studies are ongoing to evaluate the potential mechanism of mRNA transport and/or stability. Citation Format: Bandish B. Kapadia, Anirban Roychowdhury, Forum Kayastha, Nahid Nanaji, Jolene Windle, Ronald B. Gartenhaus. ALKBH5 emerges as a novel regulator of the BCR pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB049.