美国康奈尔大学Ari Melnick研究小组发现，ARID1A协调SWI/SNF介导的转录因子顺序结合，ARID1A的缺失会影响前记忆B细胞的命运和淋巴瘤的发生。该项研究成果于2024年3月7日在线发表在《癌细胞》杂志上。

研究人员表明，ARID1A能在生发中心（GC）反应过程中协调B细胞的命运，促进PU.1和NF-kB在细胞因子和CD40信号转导的关键基因上的合作和顺序结合。ARID1A的缺失会使GC细胞的命运向未成熟的IgM⁺CD80^-PD-L2^-记忆 B 细胞倾斜，众所周知，这些细胞有可能重新进入新的GC。当与BCL2致癌基因结合时，ARID1A单倍体计量不足会加速小鼠侵袭性滤泡淋巴瘤（FL）的发展。ARID1A失活突变的滤泡性淋巴瘤患者更倾向于表现出不成熟的记忆B细胞样状态，其转化为侵袭性疾病的风险增加。

这些观察结果让研究人员从机理上了解到，ARID1A突变淋巴瘤是通过形成未成熟记忆样克隆前体而出现的，既有轻度淋巴瘤，也有侵袭性淋巴瘤。最后，研究人员证明了ARID1A突变会诱导SMARCA2/4抑制的合成致死性，为高危患者的潜在精准治疗铺平了道路。

据了解，ARID1A是经典BAF核小体重塑复合物的一个亚基，在淋巴瘤中常发生突变。

附：英文原文

Title: ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis

Author: Darko Barisic, Christopher R. Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E. Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W. Scott, Andrew P. Weng, Christopher E. Mason, Michael R. Green, Ari Melnick

Issue&Volume: 2024-03-07

Abstract: ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonlymutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinalcenter (GC) response, facilitating cooperative and sequential binding of PU.1 andNF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tiltsGC cell fate toward immature IgM+CD80PD-L2 memory B cells, known for their potential to re-enter new GCs. When combined withBCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs)in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like statewith increased transformation risk to aggressive disease. These observations offermechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors.Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4inhibition, paving the way for potential precision therapy for high-risk patients.

DOI: 10.1016/j.ccell.2024.02.010

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00054-0