美国德克萨斯大学Michael R. Green课题组发现，SMARCA4是一种单倍体不足的B细胞淋巴瘤肿瘤抑制因子，可微调中心细胞的命运决定。相关论文于2024年3月7日在线发表在《癌细胞》杂志上。

研究人员表示，SMARCA4编码BRG/BRM相关因子（BAF）复合物中两个相互排斥的ATP酶亚基之一，该复合物被转录因子（TF）招募，以驱动染色质可及性和转录激活。SMARCA4是人类癌症中最常发生突变的基因之一，包括30%的生发中心（GC）来源的伯奇氏淋巴瘤。

研究人员发现，在小鼠中，GC特异性Smarca4单倍体不足与MYC过度表达共同驱动淋巴瘤的发生。此外，单等位基因的Smarca4缺失通过显著增加中心细胞向暗区循环的速率，促使GC增生，并使中心细胞极化。

从机制上讲，Smarca4缺失降低了中心细胞中被激活的TF的活性，这些TF可驱动GC退出，包括SPI1 (PU.1)、IRF家族和NF-κB。这些因子失去活性后，小鼠中心细胞和人类伯奇氏淋巴瘤细胞中的BCL6活性就会出现异常。因此，SMARCA4有利于塑造中心细胞轨迹的TF染色质可及性，而失去对这些程序的精细控制则会偏向于生发中心母细胞命运、GC增生和淋巴瘤。

附：英文原文

Title: SMARCA4 is a haploinsufficient B cell lymphoma tumor suppressor that fine-tunes centrocyte cell fate decisions

Author: Qing Deng, Priya Lakra, Panhong Gou, Haopeng Yang, Cem Meydan, Matthew Teater, Christopher Chin, Wenchao Zhang, Tommy Dinh, Usama Hussein, Xubin Li, Estela Rojas, Weiguang Liu, Patrick K. Reville, Atish Kizhakeyil, Darko Barisic, Sydney Parsons, Ashley Wilson, Jared Henderson, Brooks Scull, Channabasavaiah Gurumurthy, Francisco Vega, Amy Chadburn, Branko Cuglievan, Nader Kim El-Mallawany, Carl Allen, Christopher Mason, Ari Melnick, Michael R. Green

Issue&Volume: 2024-03-07

Abstract: SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ～30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.

DOI: 10.1016/j.ccell.2024.02.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00055-2