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 - Funding Information:
We thank all members of the Aifantis laboratory for discussions throughout this project. M.T.W. was supported by the Leukemia & Lymphoma Society Career Development Program, American Society of Hematology Restart Award, NIH/National Cancer Institute (NCI) K22 award (no. 1K22CA258520-01), Cancer League of Colorado Research Grant (AWD no. 222549) and the Jeffrey Pride Foundation for Pediatric Cancer Research and the Children’s Oncology Group Foundation. P.T. was supported by the AACR Incyte Corporation Leukemia Research Fellowship and Young Investigator grant from Alex’s Lemonade Stand Cancer Research Foundation. This work is supported by the National Science Foundation (grant no. CBET 2103219 to W.C.) and the US NIH (grant no. R35GM133646 to W.C.). C.M. is supported by the Cancer Research Institute Irvington Postdoctoral Fellowship (no. CRI4018). S.J.H is supported by an investigator grant from the National Health and Medical Research Council of Australia. J.B. is grateful for support from the NIH (grant no. 1F32HD078029-01A1). K.H. was supported by funds from Massachusetts General Hospital, the NIH (grant no. P01GM099134) and the Gerald and Darlene Jordan Chair in Regenerative Medicine. N.T. was supported by a fellowship from the German Research Foundation. A.T. and J.E. received funding from the Parker Institute for Cancer Immunotherapy and the Grand Multiple Myeloma Translational Initiative. C.G.M. was supported by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, NCI (grant no. R35 CA197695) and the Henry Schueler 41&9 Foundation. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. S.N. was supported by the Onassis Foundation—scholarship ID: F ZP 036-1/2019-2020. O.A.-W. was supported by the NIH (grant nos. R01CA251138 and R01CA242020), and the NIH/NCI (grant no. 1P50 254838-01), the Leukemia & Lymphoma Society and the Edward P. Evans MDS Foundation. I.A. was supported by the NCI/NIH (grant nos. P01CA229086, RO1CA252239, R01CA228135, R01CA242020 and O1CA266212), Curing Kids Cancer, the Leukemia and Lymphoma Society and the Vogelstein Foundation. We thank the NYU School of Medicine core facilities, including the Applied Bioinformatics Laboratories, Flow Cytometry and the Genome Technology Center (this shared resource is partially supported by the Cancer Center Support, grant no. P30CA016087, at the Laura and Isaac Perlmutter Cancer Center). Schematic illustrations in Extended Data Figs. and created with BioRender.com.
Funding Information:
We thank all members of the Aifantis laboratory for discussions throughout this project. M.T.W. was supported by the Leukemia & Lymphoma Society Career Development Program, American Society of Hematology Restart Award, NIH/National Cancer Institute (NCI) K22 award (no. 1K22CA258520-01), Cancer League of Colorado Research Grant (AWD no. 222549) and the Jeffrey Pride Foundation for Pediatric Cancer Research and the Children’s Oncology Group Foundation. P.T. was supported by the AACR Incyte Corporation Leukemia Research Fellowship and Young Investigator grant from Alex’s Lemonade Stand Cancer Research Foundation. This work is supported by the National Science Foundation (grant no. CBET 2103219 to W.C.) and the US NIH (grant no. R35GM133646 to W.C.). C.M. is supported by the Cancer Research Institute Irvington Postdoctoral Fellowship (no. CRI4018). S.J.H is supported by an investigator grant from the National Health and Medical Research Council of Australia. J.B. is grateful for support from the NIH (grant no. 1F32HD078029-01A1). K.H. was supported by funds from Massachusetts General Hospital, the NIH (grant no. P01GM099134) and the Gerald and Darlene Jordan Chair in Regenerative Medicine. N.T. was supported by a fellowship from the German Research Foundation. A.T. and J.E. received funding from the Parker Institute for Cancer Immunotherapy and the Grand Multiple Myeloma Translational Initiative. C.G.M. was supported by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, NCI (grant no. R35 CA197695) and the Henry Schueler 41&9 Foundation. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. S.N. was supported by the Onassis Foundation—scholarship ID: F ZP 036-1/2019-2020. O.A.-W. was supported by the NIH (grant nos. R01CA251138 and R01CA242020), and the NIH/NCI (grant no. 1P50 254838-01), the Leukemia & Lymphoma Society and the Edward P. Evans MDS Foundation. I.A. was supported by the NCI/NIH (grant nos. P01CA229086, RO1CA252239, R01CA228135, R01CA242020 and O1CA266212), Curing Kids Cancer, the Leukemia and Lymphoma Society and the Vogelstein Foundation. We thank the NYU School of Medicine core facilities, including the Applied Bioinformatics Laboratories, Flow Cytometry and the Genome Technology Center (this shared resource is partially supported by the Cancer Center Support, grant no. P30CA016087, at the Laura and Isaac Perlmutter Cancer Center). Schematic illustrations in Extended Data Figs. 1a,g and 6a created with BioRender.com.
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.
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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 -