Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Abstract

Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding "splicing and myeloproliferative neoplasms". We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

Keywords: epigenetic; myeloproliferative neoplasm; splicing.

Figure 1

Schematic representation of spliceosome complexes. (A) Representation of U1 snRNP, U2 snRNP and auxiliary factors fixation on pre-mRNA (major spliceosome). U1 snRNP recognizes the 5′-splice site. U2snRNP recognizes the 3′-splice site at conserved sequence positions: the branch-point, the poly-pyrimidine-tract (Py-tract), and the AG dinucleotide thanks to SF3B1 in SF3B complex, U2AF2 and U2AF1 respectively. SRSF2 binds to exonic splicing enhancer (ESE) to favor recognition and fixation of U1 and U2 snRNP. ZRSR2 promotes major spliceosome assembly. (B) U1 snRNP and U2 snRNP joining allows the 5′-splice site to interact with the branch point. (C) U11 and U12 snRNP belong to the minor spliceosome that is involved in U12-intron splicing. U12-introns are delimited by sequences at 5′ (GU or AU) and 3′ (AG or AC) splice sites different from those present in U2-introns. ZRSR2 promotes minor spliceosome assembly.

Figure 2

Examples of splicing events. From the top: cassette exon, mutually exclusive exons, alternative 5′ and 3′-splice sites, and intron retention.