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

  • Myelodysplastic Syndromes (D Steensma, Section Editor)
  • Published:
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Abstract

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.

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Authors and Affiliations

  1. Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK

    Charlotte K. Brierley

  2. Adult Leukemia Program, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, D2037, 450 Brookline Ave, Boston, MA, 02215, USA

    David P. Steensma

  3. Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA

    David P. Steensma

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Correspondence to David P. Steensma.

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Charlotte K. Brierley declares no potential conflicts of interest. David P. Steensma is a section editor for Current Hematologic Malignancy Reports.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Myelodysplastic Syndromes

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Brierley, C.K., Steensma, D.P. Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms. Curr Hematol Malig Rep 11, 408–415 (2016). https://doi.org/10.1007/s11899-016-0344-z

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