TY - JOUR
T1 - NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia
AU - Witkowski, Matthew T.
AU - Lee, Soobeom
AU - Wang, Eric
AU - Lee, Anna K.
AU - Talbot, Alexis
AU - Ma, Chao
AU - Tsopoulidis, Nikolaos
AU - Brumbaugh, Justin
AU - Zhao, Yaqi
AU - Roberts, Kathryn G.
AU - Hogg, Simon J.
AU - Nomikou, Sofia
AU - Ghebrechristos, Yohana E.
AU - Thandapani, Palaniraja
AU - Mullighan, Charles G.
AU - Hochedlinger, Konrad
AU - Chen, Weiqiang
AU - Abdel-Wahab, Omar
AU - Eyquem, Justin
AU - Aifantis, Iannis
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85138536591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138536591&partnerID=8YFLogxK
U2 - 10.1038/s41590-022-01314-y
DO - 10.1038/s41590-022-01314-y
M3 - Article
C2 - 36138187
AN - SCOPUS:85138536591
SN - 1529-2908
VL - 23
SP - 1424
EP - 1432
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -