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Haematologica 2021 Volume 106(3):736-745
Plasma Cell Disorders
Differential RNA splicing as a potentially important driver mechanism in multiple myeloma
Michael A. Bauer,1 Cody Ashby,1 Christopher Wardell,1 Eileen M. Boyle,1 Maria Ortiz,2 Erin Flynt,3 Anjan Thakurta,3 Gareth Morgan4
and Brian A. Walker1,5
1University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Celgene Institute for Translational Research Europe, Sevilla, Spain; 3Translational Development and Diagnostics, Celgene Corporation, Summit, NJ, USA; 4NYU Langone Medical Center, Perlmuter Cancer Center, NYU Langone Health, New York, NY, USA and 5Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA
ABSTRACT
Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple myeloma is a molecularly het- erogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We looked at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in com- parison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enu- meration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
Introduction
Multiple myeloma (MM) is a plasma cell disorder and is the second most com- mon hematological malignancy diagnosed in the United States. MM is character- ized by primary etiologic events involving the gain of odd numbered chromo- somes seen in 50% of patients and structural variants involving rearrangement to the immunoglobulin loci. These structural variants result in the relocation of a super-enhancer in proximity to an oncogene, resulting in its over-expression. These events subdivide non-hyperdiploid MM into 5 main groups: t(4;14) (12%), t(6;14) (1%), t(11;14) (15%), t(14;16) (3%) and t(14;20) (2%).1,2 Despite extensive work to characterize the myeloma genome, sequencing studies have only identi- fied 63 key driver genes.1 The median number of driver events per sample is five, but in a subset of samples none are detectable suggesting that we are missing driv- ers. Missing drivers may either be located in the non-coding genome or involve a mechanism that is difficult to demonstrate. Alternative splicing is one such mech- anism that has the potential to be a significant driver of disease.3-7 It is estimated that 90% of protein-coding genes undergo alternative splicing to produce multiple transcripts.8 Disruption of the splicing mechanism has the potential to have a large impact on the transcriptome and ultimately key regulatory pathways.
The spliceosome comprises a multi-component enzyme system that facilitates the splicing of pre-mRNA. The spliceosome removes an intron and subsequently ligates the proximal 5’ and 3’ exons. An intron is identified by the spliceosome through the recognition of four consensus elements which include: the 5’ splice
Correspondence:
MICHAEL A. BAUER
mbauer2@uams.edu
Received: September 13, 2019. Accepted: February 12, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.235424
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