1. NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
- Author
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Witkowski MT, Lee S, Wang E, Lee AK, Talbot A, Ma C, Tsopoulidis N, Brumbaugh J, Zhao Y, Roberts KG, Hogg SJ, Nomikou S, Ghebrechristos YE, Thandapani P, Mullighan CG, Hochedlinger K, Chen W, Abdel-Wahab O, Eyquem J, and Aifantis I
- Subjects
- Antigens, CD19 genetics, Antigens, CD19 metabolism, Cleavage And Polyadenylation Specificity Factor metabolism, Humans, Immunotherapy, Adoptive adverse effects, Membrane Glycoproteins metabolism, Polyadenylation, RNA, Messenger genetics, RNA, Messenger metabolism, Trans-Activators metabolism, Burkitt Lymphoma, Lymphoma, B-Cell, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Receptors, Chimeric Antigen metabolism
- Abstract
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., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2022
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