RNA-binding proteins of COSMIC importance in cancer

Choi, Peter S.; Thomas-Tikhonenko, Andrei

doi:10.1172/jci151627

Cited by 24 publications

(15 citation statements)

References 192 publications

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“…Interestingly, exon 2 splice site mutations were observed in the relapse sample that had not demonstrated significant AS-mediated antigen escape. Conversely, they were not detectable by RNA-seq in the relapse sample with strong evidence of AS-associated escape, suggesting that CD22 splicing dysregulation can occur by both “slow” mutational and “fast” nonmutational mechanisms, such as well-documented dysregulation of RNA-binding proteins ( 43 ). The recent emergence of inotuzumab as a potential first-line therapeutic agent for patients with B-ALL ( 15 ) will undoubtedly provide additional specimens for experimental study to elucidate the molecular mechanisms of CD22 AS.…”

Section: Discussionmentioning

confidence: 99%

Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies

Zheng

Gillespie

Naqvi

et al. 2022

Blood Cancer Discovery

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Downregulation of surface epitopes causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma membrane–bound CD22 Δex5–6 splice isoform, which is resistant to chimeric antigen receptor (CAR) T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein, thereby defining an event that is rate limiting for epitope presentation. Indeed, forcing exon 2 skipping with morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody–drug conjugate inotuzumab ozogamicin in vitro. Furthermore, among inotuzumab-treated pediatric patients with B-ALL, we identified one nonresponder in whose leukemic blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy. Significance: The mechanism(s) underlying downregulation of surface CD22 following CD22-directed immunotherapy remains underexplored. Our biochemical and correlative studies demonstrate that in B-ALL, CD22 expression levels are controlled by inclusion/skipping of CD22 exon 2. Thus, aberrant splicing of CD22 is an important driver/biomarker of de novo and acquired resistance to CD22-directed immunotherapies. See related commentary by Bourcier and Abdel-Wahab, p. 87. This article is highlighted in the In This Issue feature, p. 85

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Section: Discussionmentioning

confidence: 99%

Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies

Zheng

Gillespie

Naqvi

et al. 2022

Blood Cancer Discovery

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“…Although the functions of TFs in cancer are well studied, the role of TFs in RNA-binding activities is less clear. Several RBPs that are required for complete RNA metabolism from production to degradation are mutated in cancer; however, only a few are recognized as major cancer drivers ( 49 ). Arid5a, which functions as a TF and RBP, was recently shown to be involved in cancer.…”

Section: Arid5a-mediated Regulation Of Inflammatory Genesmentioning

confidence: 99%

Recent Advances in the Role of Arid5a in Immune Diseases and Cancer

Nyati

Kishimoto

2022

Front. Immunol.

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AT-rich interactive domain 5a (Arid5a) is a nucleic acid binding protein. In this review, we highlight recent advances in the association of Arid5a with inflammation and human diseases. Arid5a is known as a protein that performs dual functions. In in vitro and in vivo studies, it was found that an inflammation-dependent increase in Arid5a expression mediates both transcriptional and post-transcriptional regulatory effects that are implicated in immune regulation and cellular homeostasis. A series of publications demonstrated that inhibiting Arid5a augmented several processes, such as preventing septic shock, experimental autoimmune encephalomyelitis, acute lung injury, invasion and metastasis, immune evasion, epithelial-to-mesenchymal transition, and the M1-like tumor-associated macrophage (TAM) to M2-like TAM transition. In addition, Arid5a controls adipogenesis and obesity in mice to maintain metabolic homeostasis. Taken together, recent progress indicates that Arid5a exhibits multifaceted, both beneficial and detrimental, roles in health and disease and suggest the relevance of Arid5a as a potential therapeutic target.

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“… 1 Recently, the roles of RBPs and their partners in cancer progression and treatment including chemotherapy and chemoresistance attracted much attention. 2 , 3 RBPs were once considered largely “undruggable”, but currently small molecules or chemically modified antisense oligonucleotides targeting RBPs have been characterized for the treatment of certain diseases. 4 , 5 For example, recent studies have proposed several RBP-based treatments in breast cancer, such as spliceosome- and estrogen receptor α-targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis

Zhu

Chen

et al. 2022

Sig Transduct Target Ther

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RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma (HCC), pancreatic cancer and colon cancer. ZCCHC4 promotes chemoresistance of HCC cells to DNA-damage agent (DDA) both in vitro and in vivo. HCC cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDA-induced antitumor effect. Mechanistically, ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA (lncRNA) AL133467.2 to hamper its pro-apoptotic function. Also, ZCCHC4 blocks the interaction between AL133467.2 and γH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and γH2AX interaction for enhancing chemosensitivity in HCC cells. Together, our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects, providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.

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RNA-binding proteins of COSMIC importance in cancer

Cited by 24 publications

References 192 publications

Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies

Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies

Recent Advances in the Role of Arid5a in Immune Diseases and Cancer

RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis

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