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

// Heba A. Alkhatabi 1, 2 , Donal P. McLornan 1, 3 , Austin G. Kulasekararaj 1, 3 , Farooq Malik 1 , Thomas Seidl 1 , David Darling 1 , Joop Gaken 1, * , Ghulam J. Mufti 1, 3, * 1 Department of Haematological Medicine, King’s College London School of Medicine, London, UK 2 Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah, Saudi Arabia 3 Department of Hematology, King’s College Hospital, London, UK * These authors have contributed equally and share senior authorship Correspondence to: Ghulam J. Mufti, email: ghulam.mufti@kcl.ac.uk 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.