德国法兰克福大学Thomas Oellerich等研究人员合作发现，侵袭性淋巴瘤患者对布鲁顿酪氨酸激酶抑制剂的反应与慢性选择性自噬有关。相关论文于2024年1月11日在线发表在《癌细胞》杂志上。

研究人员表示，弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性极强的异质性癌症，给精准医疗带来了挑战。布鲁顿酪氨酸激酶（BTK）抑制剂可阻断B细胞受体（BCR）信号传导，对某些依赖慢性活跃BCR信号传导促进致癌NF-κB的DLBCL分子亚型特别有效。MCD基因亚型通常在BCR亚基CD79B和先天性免疫适配器MYD88^L265P中发生突变，它通常对化疗有抵抗力，但对BTK抑制剂的反应特别好。然而，人们对BTK抑制剂反应的内在机制知之甚少。

研究人员发现MCD DLBCL 中存在一种非经典形式的慢性选择性自噬，它以TBK1依赖性方式靶向泛素化的MYD88^L265P进行降解。MCD肿瘤的基因和表观遗传学改变削弱了这种自噬抑瘤途径。与此相反，BTK抑制剂能促进MYD88^L265P的自噬降解，因此在MCD DLBCL中具有特殊的临床疗效。

附：英文原文

Title: Response to Bruton’s tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy

Author: James D. Phelan, Sebastian Scheich, Jaewoo Choi, George W. Wright, Bjrn Hupl, Ryan M. Young, Sara A. Rieke, Martine Pape, Yanlong Ji, Henning Urlaub, Arnold Bolomsky, Carmen Doebele, Alena Zindel, Tanja Wotapek, Monica Kasbekar, Brett Collinge, Da Wei Huang, Zana A. Coulibaly, Vivian M. Morris, Xiaoxuan Zhuang, Julius C. Enssle, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Zhuo Wang, Andy D. Tran, Christopher J. Shoemaker, Galina Shevchenko, Daniel J. Hodson, Arthur L. Shaffer, Louis M. Staudt, Thomas Oellerich

Issue&Volume: 2024-01-11

Abstract: Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer,presenting a challenge for precision medicine. Bruton’s tyrosine kinase (BTK) inhibitorsblock B cell receptor (BCR) signaling and are particularly effective in certain molecularsubtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB.The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B,and in the innate immune adapter, MYD88L265P, typically resists chemotherapy but responds exceptionally to BTK inhibitors. However,the underlying mechanisms of response to BTK inhibitors are poorly understood. Herein,we find a non-canonical form of chronic selective autophagy in MCD DLBCL that targetsubiquitinated MYD88L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigeneticalterations that attenuate this autophagic tumor suppressive pathway. In contrast,BTK inhibitors promote autophagic degradation of MYD88L265P, thus explaining their exceptional clinical benefit in MCD DLBCL.

DOI: 10.1016/j.ccell.2023.12.019

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00447-6