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; Tsopoulidis, Nikolaos; Brumbaugh, Justin; Zhao, Yaqi; Roberts, Kathryn G.; Hogg, Simon J.; Nomikou, Sofia; Ghebrechristos, Yohana; Thandapani, Palaniraja; Mullighan, Charles G.; Hochedlinger, Konrad; Chen, Weiqiang; Abdel-Wahab, Omar; Eyquem, Justin; Aifantis, Iannis

doi:10.1038/s41590-022-01314-y

Cited by 18 publications

(19 citation statements)

References 56 publications

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“…3A ), albeit less frequent, suggesting PAX5-independent mechanisms of CD58 regulation, which are yet to be identified. PAX5 is a known transcriptional regulator of CD19 expression ( 32 , 40 ), which was also confirmed in our TF screen for CD19, although it was not one of the top hits as seen with the CD58 screen (table S2). It is likely that PAX5 modulates both CD19 and CD58 in B cells, but the exact impact may vary depending on cellular context (e.g., B-ALL subtype).…”

Section: Discussionsupporting

confidence: 67%

“…Although the work presented here largely focused on CD58, the mechanism of blinatumomab resistance is undoubtedly multifactorial and likely to involve other genes (32). For example, our CRISPR screen at blinatumomab (100 ng/ml) yielded a relatively smaller number of hits because of the small number of cells that survived this level of cytotoxic pressure.…”

Section: Discussionmentioning

confidence: 99%

“…These findings established the role of CD58 in the blinatumomab-induced immune response of effector T cells and suggested the possibility of individualizing blinatumomab therapy based on genomic findings in ALL cells. Although the work presented here largely focused on CD58, the mechanism of blinatumomab resistance is undoubtedly multifactorial and likely to involve other genes ( 32 ). For example, our CRISPR screen at blinatumomab (100 ng/ml) yielded a relatively smaller number of hits because of the small number of cells that survived this level of cytotoxic pressure.…”

Section: Discussionmentioning

confidence: 99%

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PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

Moriyama

Yoshimura

et al. 2022

Sci. Adv.

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Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19 . Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

Moriyama

Yoshimura

et al. 2022

Sci. Adv.

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“…A recent work published by Witkowski et al. on Nature Immunology also reported the negative role of Nudt21 in chimeric antigen receptor T cell therapy (CAR-T) ( 102 ). They foung that NUDT21 limits CD19 levels through alternative mRNA polyad xsenylation in B cell acute lymphoblastic leukemia.Nudt21 has been reported to both prohibit and promote tumor progression.In many cancers, NUDT21 acts as a tumor suppressor.…”

Section: Nudt21 and Apa And Tumormentioning

confidence: 99%

Relationship between NUDT21 mediated alternative polyadenylation process and tumor

Xiao

Gu²,

Deng³

et al. 2023

Front. Oncol.

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Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3’ end of RNA polymerase II transcripts from over 60% of human genes. APA and microRNA regulation are both mechanisms of post-transcriptional regulation of gene expression. As a key molecular mechanism, Alternative polyadenylation often results in mRNA isoforms with the same coding sequence but different lengths of 3’ UTRs, while microRNAs regulate gene expression by binding to specific mRNA 3’ UTRs. Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA). Different studies have reported a dual role of NUDT21 in cancer (both oncogenic and tumor suppressor). The present review focuses on the functions of APA, miRNA and their interaction and roles in development of different types of tumors.NUDT21 mediated 3’ UTR-APA changes can be used to generate specific signatures that can be used as potential biomarkers in development and disease. Due to the emerging role of NUDT21 as a regulator of the aforementioned RNA processing events, modulation of NUDT21 levels may be a novel viable therapeutic approach.

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“…1a, middle and Extended Data Fig. 1a,b) and fabricated using replica molding [28][29][30]. The chip was populated with human hematopoietic cells (bone marrow mononuclear cells), leukemia blasts, stromal cells (vascular cells, mesenchymal stem cells, osteoblasts, and fibroblasts) within compartmentalized fibrin hydrogels inside which the seeded bone marrow stromal cells rebuilt and supported the three concentric tissue structures (Methods).…”

Section: Engineering An Ex Vivo Immunocompetent Human Leukemia Chipmentioning

confidence: 99%

A bioengineered immunocompetent human leukemia chip for preclinical screening of CAR T cell immunotherapy

Chen

Wang

et al. 2023

Preprint

Self Cite

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Chimeric antigen receptor (CAR) T cell immunotherapy is promising for treatment of blood cancers; however, clinical benefits remain unpredictable, necessitating development of optimal CAR T cell products. Unfortunately, current preclinical evaluation platforms are inadequate due to their limited physiological relevance to humans. We herein engineered an organotypic immunocompetent chip that recapitulates microarchitectural and pathophysiological characteristics of human leukemia bone marrow stromal and immune niches for CAR T cell therapy modeling. This leukemia chip empowered real-time spatiotemporal monitoring of CAR T cell functionality, including T cell extravasation, recognition of leukemia, immune activation, cytotoxicity, and killing. We next on-chip modelled and mapped different responses post CAR T cell therapy, i.e., remission, resistance, and relapse as observed clinically and identify factors that potentially drive therapeutic failure. Finally, we developed a matrix-based analytical and integrative index to demarcate functional performance of CAR T cells with different CAR designs and generations produced from healthy donors and patients. Together, our chip introduces an enabling ‘(pre-)clinical-trial-on-chip’ tool for CAR T cell development, which may translate to personalized therapies and improved clinical decision-making.

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

Cited by 18 publications

References 56 publications

PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia

Relationship between NUDT21 mediated alternative polyadenylation process and tumor

A bioengineered immunocompetent human leukemia chip for preclinical screening of CAR T cell immunotherapy

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