BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.
BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.
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DOI：
10.1158/2159-8290.cd-21-1566
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发表时间：
2022-08-05
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影响因子：
28.2
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中科院分区：
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弥漫性大B细胞淋巴瘤（DLBCL）中的BCL 10突变分为两类，两者均赋予BTK抑制剂抗性，但仅截短突变赋予MALT 1依赖性，这表明使用这些突变类别作为精确治疗生物标志物。活化的B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）具有不利的结局和由于BCL 10亚基聚合而形成的CARD 11-BCL 10-MALT 1（CBM）信号放大复合物的慢性活化，这受到ABC-DLBCL中复发性体细胞突变的影响。在此，我们表明，BCL 10突变体属于至少两个功能不同的类：错义突变的BCL 10 CARD域和截断其C-末端尾巴。截短突变废除了MALT 1抑制BCL 10聚合的基序，将MALT 1捕获在其活化的免疫结合状态。CARD错义突变增强BCL 10细丝形成，形成稳定BCL 10细丝的谷氨酰胺网络结构。BCL 10的突变形式较少依赖于上游CARD 11活化，因此表现出对BTK抑制剂的抗性，而BCL 10截短突变体而非CARD突变体对MALT 1抑制剂超敏。因此，BCL 10突变是ABC-DLBCL中BTK抑制剂耐药性的潜在生物标志物，并且可以通过基于不同突变类别的特定生化作用选择疗法来实现进一步的精确度。ABC-DLBCL的特点是信号传导介质的频繁突变，这些突变聚集在CBM复合物上。我们使用结构-功能的方法来揭示BCL 10突变分为两个不同的生化类。这两种类型都赋予对BTK抑制剂的抗性，而BCL 10截短赋予对MALT 1抑制剂的高反应性，为ABC-DLBCL的精确治疗提供了路线图。 参见Dallan和Oellerich的相关评注，第1844页。 这篇文章在本期专题中突出显示，第1825页
BCL10 mutations in diffuse large B-cell lymphoma (DLBCL) fall into two classes, with both conferring BTK inhibitor resistance but only truncation mutations conferring MALT1 dependency, suggesting use of these mutation classes as precision therapy biomarkers. Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure–function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825