Blinatumoab公司
CD19
癌症研究
生物
免疫疗法
B细胞
T细胞
聚腺苷酸
免疫学
抗原
分子生物学
信使核糖核酸
抗体
免疫系统
遗传学
基因
作者
Matthew T Witkowski,Soobeom Lee,Eric Wang,Anna K. Lee,Alexis Talbot,Chao Ma,Nikolaos Tsopoulidis,Justin Brumbaugh,Yaqi Zhao,Kathryn G. Roberts,Simon J. Hogg,Sofia Nomikou,Yohana Ghebrechristos,Palaniraja Thandapani,Charles G. Mullighan,Konrad Hochedlinger,Weiqiang Chen,Omar Abdel-Wahab,Justin Eyquem,Iannis Aifantis
标识
DOI:10.1038/s41590-022-01314-y
摘要
B cell progenitor acute lymphoblastic leukemia (B-ALL) treatment has been revolutionized by T cell-based immunotherapies-including chimeric antigen receptor T cell therapy (CAR-T) and the bispecific T cell engager therapeutic, blinatumomab-targeting surface glycoprotein CD19. Unfortunately, many patients with B-ALL will fail immunotherapy due to 'antigen escape'-the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. In the present study, we utilized a genome-wide CRISPR-Cas9 screening approach to identify modulators of CD19 abundance on human B-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 messenger RNA polyadenylation and stability. NUDT21 deletion in B-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human B-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify new CD19 modulators in human B-ALL.
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