Oncotarget

Research Papers:

RPL27A is a target of miR-595 and may contribute to the myelodysplastic phenotype through ribosomal dysgenesis

Heba A. Alkhatabi, Donal P. McLornan, Austin G. Kulasekararaj, Farooq Malik, Thomas Seidl, David Darling, Joop Gaken and Ghulam J. Mufti _

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Oncotarget. 2016; 7:47875-47890. https://doi.org/10.18632/oncotarget.10293

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Abstract

Heba A. Alkhatabi1,2, Donal P. McLornan1,3, Austin G. Kulasekararaj1,3, Farooq Malik1, Thomas Seidl1, David Darling1, Joop Gaken1,*, Ghulam J. Mufti1,3,*

1Department of Haematological Medicine, King’s College London School of Medicine, London, UK

2Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah, Saudi Arabia

3Department of Hematology, King’s College Hospital, London, UK

*These authors have contributed equally and share senior authorship

Correspondence to:

Ghulam J. Mufti, email: [email protected]

Keywords: myelodysplasia, ribosome, microRNA, haemopoiesis, chromosome

Received: March 22, 2016     Accepted: May 19, 2016     Published: June 25, 2016

ABSTRACT

We investigated the functional consequences following deletion of a microRNA (miR) termed miR-595 which resides on chromosome 7q and is localised within one of the commonly deleted regions identified for Myelodysplasia (MDS) with monosomy 7 (−7)/isolated loss of 7q (7q-). We identified several targets for miR-595, including a large ribosomal subunit protein RPL27A. RPL27A downregulation induced p53 activation, apoptosis and inhibited proliferation. Moreover, p53-independent effects were additionally identified secondary to a reduction in the ribosome subunit 60s. We confirmed that RPL27A plays a pivotal role in the maintenance of nucleolar integrity and ribosomal synthesis/maturation. Of note, RPL27A overexpression, despite showing no significant effects on p53 mRNA levels, did in fact enhance cellular proliferation. In normal CD34+ cells, RPL27A knockdown preferentially blocked erythroid proliferation and differentiation. Lastly, we show that miR-595 expression appears significantly downregulated in the majority of primary samples derived from MDS patients with (−7)/(7q-), in association with RPL27A upregulation. This significant downregulation of miR-595 is also apparent when higher risk MDS cases are compared to lower risk cases. The potential clinical importance of these findings requires further validation.


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