Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications
Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications
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DOI：
10.1038/s41375-019-0571-0
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发表时间：
2020-02-01
期刊：
影响因子：
11.4
通讯作者：
Deaglio, Silvia
中科院分区：
文献类型：
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作者：
Arruga, Francesca;Bracciama, Valeria;Deaglio, Silvia
慢性淋巴细胞白血病（CLL）中的NOTCH 1突变导致NOTCH 1胞内结构域（NICD）的积累并延长信号传导。与野生型（WT）CLL相比，这些突变与更具侵袭性的疾病相关。在这项工作中，我们证明了NOTCH 1和B细胞受体（BCR）途径之间的双向功能关系。通过使用原代CLL细胞的高度同质群组，显示NOTCH 1的活化增加表面IgM以及林恩、BTK和BLNK的表达，最终增强BCR信号传导应答，包括整体mRNA翻译。在BCR交联后，NOTCH 1本身在细胞表面被主动翻译并增加。此外，BCR连接诱导钙动员，这可以促进配体非依赖性NOTCH 1活化。这些数据表明，这两种途径在功能上是联系在一起的，为双重抑制策略提供了依据。一致，添加。-分泌酶抑制剂DAPT与伊曲替尼的联合使用在体外和短期患者来源的异种移植模型中均显著增强其作用。虽然这一观察结果在CLL领域的应用可能有限，但它与里希特综合征（RS）管理更相关，其中很少有成功的治疗选择。用伊曲替尼和DAPT的组合治疗RS患者来源的异种移植物（RSPDX）降低了疾病负担并增加了总生存期。
NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the.-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RSPDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.