NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia Research Letter

   


Authors: Witkowski, M. T.; Lee, S.; Wang, E.; Lee, A. K.; Talbot, A.; Ma, C.; Tsopoulidis, N.; Brumbaugh, J.; Zhao, Y.; Roberts, K. G.; Hogg, S. J.; Nomikou, S.; Ghebrechristos, Y. E.; Thandapani, P.; Mullighan, C. G.; Hochedlinger, K.; Chen, W.; Abdel-Wahab, O.; Eyquem, J.; Aifantis, I.
Title: NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia
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.
Keywords: genetics; metabolism; acute lymphoblastic leukemia; b cell lymphoma; lymphoma, b-cell; messenger rna; rna, messenger; membrane glycoproteins; transactivator protein; membrane protein; precursor cell lymphoblastic leukemia-lymphoma; trans-activators; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; burkitt lymphoma; antigens, cd19; adverse event; polyadenylation; cleavage and polyadenylation specificity factor; humans; human; receptors, chimeric antigen; nudt21 protein, human; znf143 protein, human
Journal Title: Nature Immunology
Volume: 23
Issue: 10
ISSN: 1529-2908
Publisher: Nature Publishing Group  
Date Published: 2022-10-01
Start Page: 1424
End Page: 1432
Language: English
DOI: 10.1038/s41590-022-01314-y
PUBMED: 36138187
PROVIDER: scopus
PMCID: PMC9611506
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85138536591&doi=10.1038%2fs41590-022-01314-y&partnerID=40&md5=34497aea964109462ac22c6ca785eb59
Notes: Article -- Export Date: 1 November 2022 -- Source: Scopus
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MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    582 Abdel-Wahab
  2. Simon John Hogg
    26 Hogg
  3. Eric Wang
    12 Wang
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