Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms

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• 作者：Charlotte K. Brierley ; David P. Steensma
• 关键词：Splicing ; Myelodysplastic syndromes ; SF3B1 ; E7107 ; Targeted therapy
• 刊名：Current Hematologic Malignancy Reports
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：11
• 期：6
• 页码：408-415
• 全文大小：
• 刊物主题：Hematology; Oncology; Geriatrics/Gerontology;
• 出版者：Springer US
• ISSN：1558-822X
• 卷排序：11

文摘

Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016.