Oncotarget

Research Papers:

Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations

Derya Aslan, Christian Garde, Mette Katrine Nygaard, Alexandra Søgaard Helbo, Konstantinos Dimopoulos, Jakob Werner Hansen, Marianne Tang Severinsen, Marianne Bach Treppendahl, Lene Dissing Sjø, Kirsten Grønbæk, Lasse Sommer Kristensen _

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Abstract

Derya Aslan1, Christian Garde2, Mette Katrine Nygaard3, Alexandra Søgaard Helbo1, Konstantinos Dimopoulos1, Jakob Werner Hansen1, Marianne Tang Severinsen3, Marianne Bach Treppendahl1, Lene Dissing Sjø4, Kirsten Grønbæk1, Lasse Sommer Kristensen1

1Department of Hematology, Rigshospitalet, Copenhagen, Denmark

2Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark

3Department of Hematology, Aalborg University Hospital, Aalborg, Denmark

4Department of Pathology, Rigshospitalet, Copenhagen, Denmark

Correspondence to:

Lasse Sommer Kristensen, e-mail: lasse.sommer.kristensen@regionh.dk, lasse@biomed.au.dk

Keywords: myelodysplastic syndrome, microRNAs, spliceosome mutations, RT-qPCR, high-resolution melting

Received: August 23, 2015     Accepted: January 19, 2016     Published: February 02, 2016

ABSTRACT

Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR. The majority of the studied miRNAs have previously been implicated in MDS. Stably expressed miRNA genes for normalization of the data were identified using GeNorm and NormFinder algorithms. High-resolution melting assays covering all mutational hotspots within SF3B1, SRSF2, and U2AF1 (U2AF35) were developed, and all detected mutations were confirmed by Sanger sequencing. Overall, canonical miRNAs were downregulated in spliceosome mutated samples compared to wild-type (P = 0.002), and samples from spliceosome mutated patients clustered together in hierarchical cluster analyses. Among the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS.

Author Information

Derya Aslan

Christian Garde

Mette Katrine Nygaard

Alexandra Søgaard Helbo

Konstantinos Dimopoulos

Jakob Werner Hansen

Marianne Tang Severinsen

Marianne Bach Treppendahl

Lene Dissing Sjø

Kirsten Grønbæk

Lasse Sommer Kristensen
Primary Contact  _


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