Journal
NATURE IMMUNOLOGY
Volume 23, Issue 10, Pages 1424-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-022-01314-y
Keywords
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Categories
Funding
- Leukemia & Lymphoma Society Career Development Program
- American Society of Hematology Restart Award
- NIH/National Cancer Institute (NCI) K22 award [1K22CA258520-01]
- Cancer League of Colorado Research Grant [222549]
- Jeffrey Pride Foundation for Pediatric Cancer Research
- Children's Oncology Group Foundation
- AACR Incyte Corporation Leukemia Research Fellowship
- Alex's Lemonade Stand Cancer Research Foundation
- National Science Foundation [CBET 2103219]
- US NIH [R35GM133646]
- Cancer Research Institute Irvington Postdoctoral Fellowship [CRI4018]
- National Health and Medical Research Council of Australia
- NIH [1F32HD078029-01A1, P01GM099134, R01CA251138, R01CA242020]
- Massachusetts General Hospital
- Gerald and Darlene Jordan Chair in Regenerative Medicine
- German Research Foundation
- Parker Institute for Cancer Immunotherapy
- Grand Multiple Myeloma Translational Initiative
- American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, NCI [R35 CA197695]
- Henry Schueler 419 Foundation
- Onassis Foundation [F ZP 036-1/2019-2020]
- NIH/NCI [1P50 254838-01]
- Leukemia & Lymphoma Society
- Edward P. Evans MDS Foundation
- NCI/NIH [R01CA242020, P01CA229086, RO1CA252239, R01CA228135, O1CA266212]
- Curing Kids Cancer
- Leukemia and Lymphoma Society
- Vogelstein Foundation
- Laura and Isaac Perlmutter Cancer Center [P30CA016087]
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Aifantis and colleagues used leukemic cell lines to identify novel regulators of CD19 expression in B-ALL. They found that the transcriptional activator ZNF143 plays a critical role in CD19 promoter activation, while the RNA-binding protein NUDT21 limits CD19 expression through the regulation of CD19 mRNA polyadenylation and stability. Deletion of NUDT21 in B-ALL cells increased CD19 expression and sensitivity to CAR-T and blinatumomab. Clinical findings showed that upregulation of NUDT21 coincided with CD19 loss in B-ALL patients at disease relapse.
Aifantis and colleagues use leukemic cell lines to identify modulators of CD19 expression that have the potential to improve therapeutic strategies. 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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