NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
复制标题
DOI：
10.1038/s41590-022-01314-y
复制
发表时间：
2022-10
影响因子：
30.5
通讯作者：
Aifantis, Iannis
中科院分区：
文献类型：
--
作者：
Witkowski, Matthew T.;Lee, Soobeom;Wang, Eric;Lee, Anna K.;Talbot, Alexis;Ma, Chao;Tsopoulidis, Nikolaos;Brumbaugh, Justin;Zhao, Yaqi;Roberts, Kathryn G.;Hogg, Simon J.;Nomikou, Sofia;Ghebrechristos, Yohana E.;Thandapani, Palaniraja;Mullighan, Charles G.;Hochedlinger, Konrad;Chen, Weiqiang;Abdel-Wahab, Omar;Eyquem, Justin;Aifantis, Iannis
B细胞祖性急性淋巴细胞白血病（BCP-ALL）的治疗已经被基于T细胞的免疫疗法彻底改变，包括嵌合抗原受体（CAR） T细胞疗法和双特异性T细胞参与疗法，靶向表面糖蛋白CD19。不幸的是，许多B-ALL患者由于“抗原逃逸”——抗白血病T细胞靶向的白血病CD19的丢失或缺失，导致免疫治疗失败。在这里，我们利用全基因组CRISPR/Cas9筛选方法鉴定了人BCP-ALL细胞中CD19丰度的调节因子。这些研究确定了转录激活子ZNF143在CD19启动子激活中的关键作用。相反，rna结合蛋白NUDT21通过调节CD19 mRNA的聚腺苷化和稳定性来限制CD19的表达。BCP-ALL细胞中NUDT21的缺失增加了CD19的表达以及对CD19特异性CAR-T和blinatumumab的敏感性。在接受CAR-T和blinatumumab治疗的人BCP-ALL患者中，NUDT21 mRNA的上调与疾病复发时CD19的缺失相吻合。总之，这些研究确定了人类BCP-ALL中新的CD19调节剂。Aifantis及其同事使用白血病细胞系来鉴定CD19表达的调节剂，这些调节剂有可能改善治疗策略。
B cell progenitor acute lymphoblastic leukemia (BCP-ALL) treatment has been revolutionized by T cell-based immunotherapies - including chimeric antigen receptor (CAR) T cell therapy and bi-specific T cell engager therapeutic, blinatumomab - targeting surface glycoprotein CD19. Unfortunately, many B-ALL patients will fail immunotherapy due to ‘antigen escape’ – the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. Here, we utilized genome-wide CRISPR/Cas9 screening approach to identify modulators of CD19 abundance on human BCP-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 mRNA polyadenylation and stability. NUDT21 deletion in BCP-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human BCP-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify novel CD19 modulators in human BCP-ALL. Aifantis and colleagues use leukemic cell lines to identify modulators of CD19 expression that have the potential to improve therapeutic strategies.
登录
查看更多内容
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
46.9
作者：
Dann, Emma;Henderson, Neil C.;Marioni, John C.
通讯作者：
Marioni, John C.