The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis

Tran, Tiffany; Philipp, Julia; Bassi, Jaspal; Nibber, Neha; Draper, Jolene M.; Lin, Tasha; Palanichamy, Jayanth Kumar; Jaiswal, Amit; Silva, Oscar; Paing, May; King, Jennifer K.; Katzman, Sol; Sanford, Jeremy R.; Rao, Dinesh S.

doi:10.1038/s41375-021-01346-7

Cited by 27 publications

(42 citation statements)

References 75 publications

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“…Thus, IGF2BP3 is an attractive therapeutic target as demonstrated in this study and other researches. 43 In addition, we found that DNA mutations regulated extensive AASEs primarily through trans-regulatory mode and most trans-sQTLs belonged to missense mutations. Especially, we noticed that the hotspot mutation of TP53 would affect a wild range of alternative splicing of other genes in LUAD, which is difficult to understand at first glance.…”

Section: Discussionmentioning

confidence: 79%

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Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Wang

et al. 2022

Sig Transduct Target Ther

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Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.

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Section: Discussionmentioning

confidence: 79%

“…Thus, IGF2BP3 is an attractive therapeutic target as demonstrated in this study and other researches. 43 …”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Wang

et al. 2022

Sig Transduct Target Ther

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“…Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of modified m 6 A RNA. 47,77 Taken together, these studies uncover the similar functional roles of different m 6 A modifiers (writers, erasers, and readers) via totally distinct mechanisms.…”

Section: Roles and Mechanisms Of M 6 A In Amlmentioning

confidence: 74%

RNA m6A modification: Mapping methods, roles, and mechanisms in acute myeloid leukemia

Yin

Tian

et al. 2022

Blood Science

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N 6 -Methyladenosine (m 6 A) is the most abundant modification in eukaryotic mRNA, and plays important biological functions via regulating RNA fate determination. Recent studies have shown that m 6 A modification plays a key role in hematologic malignancies, including acute myeloid leukemia. The current growth of epitranscriptomic research mainly benefits from technological progress in detecting RNA m 6 A modification in a transcriptome-wide manner. In this review, we first briefly summarize the latest advances in RNA m 6 A biology by focusing on writers, readers, and erasers of m 6 A modification, and describe the development of high-throughput methods for RNA m 6 A mapping. We further discuss the important roles of m 6 A modifiers in acute myeloid leukemia, and highlight the identification of potential inhibitors for AML treatment by targeting of m 6 A modifiers. Overall, this review provides a comprehensive summary of RNA m 6 A biology in acute myeloid leukemia.

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“…These results suggested that future studies should focus more on the expression of gene subtypes or different transcripts rather than the overall expression level of genes. As a member of the IGF2BPs family, a series of studies have shown that IGF2BP3 is associated with the proliferation and metastasis of colon cancer [ 41 ], bladder cancer [ 42 ], gastric cancer [ 43 ], and other malignant tumours [ 44 , 45 ]. In addition, IGF2BP3 can also participate in the regulation of mRNA stability and translation through the recognition of m 6 A sites, such as MYC, CDK6, or Cyclin D1 [ 41 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognosis-related alternative splicing events in ovarian cancer

Wang¹,

Wang

Zhang

et al. 2022

RNA Biology

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Ovarian cancer (OV) is characterized by high incidence and poor prognosis. Increasing evidence indicates that aberrant alternative splicing (AS) events are associated with the pathogenesis of cancer. We examined prognosis-related alternative splicing events and constructed a clinically applicable model to predict patients’ outcomes. Public database including The Cancer Genome Atlas (TCGA), TCGA SpliceSeq, and the Genomics of Drug Sensitivity in Cancer databases were used to detect the AS expression, immune cell infiltration and IC50. The prognosis-related AS model was constructed and validated by using Cox regression, LASSO regression, C-index, calibration plots, and ROC curves. A total of eight AS events (including FLT3LG|50942|AP) were selected to establish the prognosis-related AS model. Compared with high-risk group, low-risk group had a better outcome ( P = 1.794e-06), was more sensitive to paclitaxel ( P = 0.022), and higher proportions of plasma cells. We explored the upstream regulatory mechanisms of prognosis-related AS and found that two splicing factor and 156 tag single nucleotide polymorphisms may be involved in the regulation of prognosis-related AS. In order to assess patient prognosis more comprehensively, we constructed a clinically applicable model combining risk score and clinicopathological features, and the 1 -, and 3-year AUCs of the clinically applicable model were 0.812, and 0.726, which were 7.5% and 3.3% higher than that of the risk score. We constructed a prognostic signature for OV patients and comprehensively analysed the regulatory characteristics of the prognostic AS events in OV.

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The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis

Cited by 27 publications

References 75 publications

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

RNA m6A modification: Mapping methods, roles, and mechanisms in acute myeloid leukemia

Comprehensive analysis of prognosis-related alternative splicing events in ovarian cancer

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