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NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia
- 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
- et al.
Published Web Location
https://doi.org/10.1038/s41590-022-01314-yAbstract
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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