Molecular mechanisms by which splice modulator GEX1A inhibits leukaemia development and progression

Sellin, Mark; Mack, Ryan; Rhodes, Matthew C; Zhang, Lei; Berg, Stephanie; Joshi, Kanak; Liu, Shanhui; Wei, Wei; J, Peter Breslin S; Larsen, Peter; Taylor, Richard E.; Zhang, Jiwang

doi:10.1038/s41416-022-01796-5

Cited by 2 publications

(3 citation statements)

References 105 publications

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“…GEX1A, one of several compounds tested, upregulated SV40 and cell cycle promoter driven transcription, stalled cell cycle progression at G1 and G2/M, and reduced CDK1 mRNA length in a dose-dependent manner [62]. In vitro, GEX1A treatment resulted in variable responses across multiple leukemic cell lines, which corresponded to overall survival in pre-clinical models [63]. Hasegawa et al showed that GEX1A bound SF3B1, leading to splicing inhibition.…”

Section: Therapeutic Targeting Of Rna Splicing In Cancermentioning

confidence: 99%

“…In an attempt to understand GEX1A treatment variability, Hasegawa et al found that the alternative splicing of pro-survival mRNAs encoding MCL-1 or pro-apoptotic mRNA encoding BIM were not predicters of resistance. It was determined, however, that resistant cell lines and pre-clinical models could be sensitized to GEX1A through treatment with BCL-xL inhibitors, which resulted in a synergistic increase in apoptosis [63].…”

Section: Therapeutic Targeting Of Rna Splicing In Cancermentioning

confidence: 99%

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Therapeutic Targeting of RNA Splicing in Cancer

Bonner

Lee

2023

Genes

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RNA splicing is a key regulatory step in the proper control of gene expression. It is a highly dynamic process orchestrated by the spliceosome, a macro-molecular machinery that consists of protein and RNA components. The dysregulation of RNA splicing has been observed in many human pathologies ranging from neurodegenerative diseases to cancer. The recent identification of recurrent mutations in the core components of the spliceosome in hematologic malignancies has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. This review article will discuss our current understanding of how aberrant RNA splicing regulation drives tumor initiation and progression. We will also review current therapeutic modalities and highlight emerging technologies designed to target RNA splicing for cancer treatment.

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Section: Therapeutic Targeting Of Rna Splicing In Cancermentioning

confidence: 99%

Section: Therapeutic Targeting Of Rna Splicing In Cancermentioning

confidence: 99%

Therapeutic Targeting of RNA Splicing in Cancer

Bonner

Lee

2023

Genes

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“…Small molecule spliceosome inhibitors have great potential as a new therapeutic approach in cancer treatment. Several novel compounds (Supplementary Table 1) (81-85) targeting the RNA splicing machinery have been identified, such as pladienolides (E7017), derivatives of FR901464 (spliceostatin A, meayamycin), Herboxidiene (GEX1A) (86), Jerantinine A, OTS964, and H3B-8800, which interfere with the spliceosome complex to target specific steps in spliceosome assembly and/or catalysis. However, these drugs have not yet entered clinical use.…”

Section: Treatment Of Targeted Spliceosomesmentioning

confidence: 99%

SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process

Jiang

Chen²,

Liu³

et al. 2023

Front. Oncol.

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Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future.

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Molecular mechanisms by which splice modulator GEX1A inhibits leukaemia development and progression

Cited by 2 publications

References 105 publications

Therapeutic Targeting of RNA Splicing in Cancer

Therapeutic Targeting of RNA Splicing in Cancer

SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process

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