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

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 E. Ghebrechristos, Palaniraja Thandapani, Charles G. Mullighan, Konrad Hochedlinger, Weiqiang Chen, Omar Abdel-Wahab, Justin Eyquem, Iannis Aifantis

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1424-1432
Number of pages9
JournalNature Immunology
Issue number10
StatePublished - Oct 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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