RAG enhances BCR-ABL1-positive leukemic cell growth through its endonuclease activity in vitro and in vivo.
RAG enhances BCR-ABL1-positive leukemic cell growth through its endonuclease activity in vitro and in vivo.
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RAG 通过其体外和体内核酸内切酶活性增强 BCR-ABL1 阳性白血病细胞的生长
DOI：
10.1111/cas.14939
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发表时间：
2021-07
期刊：
影响因子：
5.7
通讯作者：
Ji Y
中科院分区：
文献类型：
--
作者：
Yuan M;Wang Y;Qin M;Zhao X;Chen X;Li D;Miao Y;Otieno Odhiambo W;Liu H;Ma Y;Ji Y
与额外DNA病变相关的BCR-ABL 1基因融合涉及慢性粒细胞白血病（CML）从慢性期（CP）到B淋巴样（CML-LBC）谱系急变和BCR-ABL 1+急性淋巴细胞白血病（BCR-ABL 1 + ALL）的发病机制。在淋巴细胞发育过程中组装不同抗原受体基因的重组激活基因RAG 1和RAG 2（统称RAG）蛋白在CML‐LBC和BCR‐ ABL 1 + ALL中异常表达。然而，RAG失调与疾病进展的直接关系尚不清楚。在这里，我们分别产生了表达人野生型（WT）RAG和无催化活性RAG的BCR-ABL 1+和BCR-ABL 1-细胞系，并证明了BCR-ABL 1特异性地与RAG重组酶合作，以促进体外和异种移植小鼠模型中的细胞存活。与无催化活性的RAG表达BCR-ABL 1+细胞系和RAG缺陷型CML-CP样本相比，WT RAG表达BCR-ABL 1+细胞系和CML-LBC样本的原代CD 34+骨髓细胞维持更多的双链断裂（DSB），这通过γ-H2 AX测量。WT RAG表达BCR-ABL 1+细胞偏向于通过替代非同源末端连接途径（a-NHEJ）修复RAG介导的DSB，这可能通过增加a-NHEJ相关MRE 11和RAD 50蛋白的表达而导致基因组不稳定性。因此，表达RAG的BCR-ABL 1+细胞通过激活BCR-ABL 1信号传导降低对酪氨酸激酶抑制剂（TKI）的敏感性，但与BCR-ABL 1表达水平和BCR-ABL 1酪氨酸激酶结构域突变无关。这些发现确定了RAG通过其核酸内切酶活性在BCR-ABL 1+白血病疾病进展的功能特化中的令人惊讶的新作用。BCR-ABL 1与RAG结合，促进BCR-ABL 1+细胞在体外和体内的存活。RAG的核酸内切酶活性驱动BCR-ABL 1+细胞选择α-NHEJ途径以响应DNA损伤。RAG刺激BCR-ABL 1信号传导以降低TKI治疗功效，尽管与BCR-ABL 1表达和BCR-ABL 1激酶结构域中的突变无关。
BCR‐ABL1 gene fusion associated with additional DNA lesions involves the pathogenesis of chronic myelogenous leukemia (CML) from a chronic phase (CP) to a blast crisis of B lymphoid (CML‐LBC) lineage and BCR‐ABL1 + acute lymphoblastic leukemia (BCR‐ABL1 + ALL). The recombination‐activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML‐LBC and BCR‐ABL1 + ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild‐type (WT) RAG and catalytically inactive RAG‐expressing BCR‐ABL1 + and BCR‐ABL1 − cell lines, respectively, and demonstrate that BCR‐ABL1 specifically collaborates with RAG recombinase to promote cell survival in vitro and in xenograft mice models. WT RAG‐expressing BCR‐ABL1 + cell lines and primary CD34+ bone marrow cells from CML‐LBC samples maintain more double‐strand breaks (DSB) compared to catalytically inactive RAG‐expressing BCR‐ABL1 + cell lines and RAG‐deficient CML‐CP samples, which are measured by γ‐H2AX. WT RAG‐expressing BCR‐ABL1 + cells are biased to repair RAG‐mediated DSB by the alternative non–homologous end joining pathway (a‐NHEJ), which could contribute genomic instability through increasing the expression of a‐NHEJ‐related MRE11 and RAD50 proteins. As a result, RAG‐expressing BCR‐ABL1 + cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR‐ABL1 signaling but independent of the levels of BCR‐ABL1 expression and mutations in the BCR‐ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in BCR‐ABL1 + leukemia through its endonuclease activity. BCR‐ABL1 associates with RAG to promote BCR‐ABL1+ cell survival in vitro and in vivo. The endonuclease activity of RAG drives BCR‐ABL1+ cells to choose the a‐NHEJ pathway in response to DNA damage. RAG stimulates BCR‐ABL1 signaling to reduce TKI therapeutic efficacy, albeit independently of BCR‐ABL1 expression and mutations in the BCR‐ABL1 kinase domain.
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影响因子：
29.7
作者：
Helmink BA;Sleckman BP
通讯作者：
Sleckman BP
影响因子：
50.3
作者：
Klemm L;Duy C;Iacobucci I;Kuchen S;von Levetzow G;Feldhahn N;Henke N;Li Z;Hoffmann TK;Kim YM;Hofmann WK;Jumaa H;Groffen J;Heisterkamp N;Martinelli G;Lieber MR;Casellas R;Müschen M
通讯作者：
Müschen M
影响因子：
64.5
作者：
Karo JM;Schatz DG;Sun JC
通讯作者：
Sun JC
AID 通过 DNA 甲基化协助 DNMT1 在弥漫性大 B 细胞淋巴瘤细胞系中减弱 BCL6 表达
影响因子：
4.8
作者：
Jiao, Junna;Lv, Zhuangwei;Ji, Yanhong
通讯作者：
Ji, Yanhong
影响因子：
4.3
作者：
Ayoub, Nabieh;Jeyasekharan, Anand D.;Venkitaraman, Ashok R.
通讯作者：
Venkitaraman, Ashok R.