Loss of AID exacerbates the malignant progression of CLL.
Loss of AID exacerbates the malignant progression of CLL.
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DOI：
10.1038/s41375-022-01663-5
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发表时间：
2022-10
期刊：
影响因子：
11.4
通讯作者：
Tang, Chih-Hang Anthony
中科院分区：
文献类型：
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作者：
Lee, Avery C.;Pingali, Sai Ravi;Pinilla-Ibarz, Javier A.;Atchison, Michael L.;Koumenis, Constantinos;Argon, Yair;Thomas-Tikhonenko, Andrei;De Trez, Carl;Hu, Chih-Chi Andrew;Tang, Chih-Hang Anthony
活化诱导的胞苷脱氨酶（AID）在B细胞慢性淋巴细胞白血病（CLL）的发生、发展过程中既有积极作用，也有消极作用，但其在CLL发生、发展过程中的作用尚不清楚。我们建立了一个AID敲除的CLL小鼠模型，AID-/-/Eμ-TCL 1，发现这些小鼠比它们的艾滋病熟练的同行死得更早。与Eμ-TCL 1对照相比，AIDS缺陷型CLL细胞表现出更高的ER应激反应，特别是通过激活IRE 1/XBP 1 s通路。分泌型IgM在AIDS缺陷型CLL细胞中的增加的产生有助于其升高的XBP 1表达水平，而分泌型IgM缺陷型CLL细胞表达较少的XBP 1。这种XBP 1的增加反过来导致AIDS缺陷型CLL细胞表现出更高水平的B细胞受体信号传导，支持白血病生长和存活。此外，AID−/−/Eμ-TCL 1 CLL细胞下调肿瘤抑制性SMAD 1/S1 PR 2通路，并改变了归巢至非淋巴器官的方式。值得注意的是，来自IgHV未突变疾病患者的CLL细胞与来自IgHV突变CLL患者的CLL细胞相比表达更高水平的XBP 1 s mRNA。因此，我们的研究揭示了AID丧失导致CLL恶化的新机制，并可能解释为什么未突变的CLL比突变的CLL更具侵袭性。
Activation-induced cytidine deaminase (AID) has been implicated as both a positive and a negative factor in the progression of B cell chronic lymphocytic leukemia (CLL), but the role that it plays in the development and progression of this disease is still unclear. We generated an AID knockout CLL mouse model, AID−/−/Eμ-TCL1, and found that these mice die significantly earlier than their AID-proficient counterparts. AID-deficient CLL cells exhibit a higher ER stress response compared to Eμ-TCL1 controls, particularly through activation of the IRE1/XBP1s pathway. The increased production of secretory IgM in AID-deficient CLL cells contributes to their elevated expression levels of XBP1s, while secretory IgM-deficient CLL cells express less XBP1s. This increase in XBP1s in turn leads AID-deficient CLL cells to exhibit higher levels of B cell receptor signaling, supporting leukemic growth and survival. Further, AID−/−/Eμ-TCL1 CLL cells downregulate the tumor suppressive SMAD1/S1PR2 pathway and have altered homing to non-lymphoid organs. Notably, CLL cells from patients with IgHV-unmutated disease express higher levels of XBP1s mRNA compared to those from patients with IgHV-mutated CLL. Our studies thus reveal novel mechanisms by which the loss of AID leads to worsened CLL and may explain why unmutated CLL is more aggressive than mutated CLL.
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影响因子：
20.3
作者：
McCarthy, H;Wierda, WG;Abruzzo, LV
通讯作者：
Abruzzo, LV
影响因子：
7.5
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Grioni, Matteo;Brevi, Arianna;Calcinotto, Arianna
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Calcinotto, Arianna
影响因子：
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作者：
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通讯作者：
Ron, D
针对 AID、APOBEC3A 和 APOBEC3B 催化袋的第一代小分子抑制剂的基于结构的设计。
影响因子：
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作者：
King JJ;Borzooee F;Im J;Asgharpour M;Ghorbani A;Diamond CP;Fifield H;Berghuis L;Larijani M
通讯作者：
Larijani M
影响因子：
30.5
作者：
通讯作者：
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