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However, we recently showed that the serine\/threonine kinase <jats:styled-content style=\"fixed-case\">PDPK<\/jats:styled-content>1 and its substrate <jats:styled-content style=\"fixed-case\">RPS<\/jats:styled-content>6<jats:styled-content style=\"fixed-case\">KA<\/jats:styled-content>3 (also termed <jats:styled-content style=\"fixed-case\">RSK<\/jats:styled-content>2) are universally active in <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR\u2010375 repression in <jats:styled-content style=\"fixed-case\">PDPK<\/jats:styled-content>1 overexpression in <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>. An analysis of plasma cells from 30 pre\u2010malignant monoclonal gammopathies of undetermined significance and 73 <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content> patients showed a significant decrease in miR\u2010375 expression in patient\u2010derived plasma cells regardless of the clinical stage, compared to normal plasma cells. Introduction of miR\u2010375 reduced <jats:styled-content style=\"fixed-case\">PDPK<\/jats:styled-content>1 expression in human myeloma cell lines (<jats:styled-content style=\"fixed-case\">HMCL<\/jats:styled-content>s), indicating that miR\u2010375 is the dominant regulator of <jats:styled-content style=\"fixed-case\">PDPK<\/jats:styled-content>1 expression. In addition, miR\u2010375 introduction also downregulated <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1R and <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2 in <jats:styled-content style=\"fixed-case\">HMCL<\/jats:styled-content>s. CpG islands in the <jats:italic><jats:styled-content style=\"fixed-case\">MIR<\/jats:styled-content>375<\/jats:italic> promoter were pathologically hypermethylated in all 8 <jats:styled-content style=\"fixed-case\">HMCL<\/jats:styled-content>s examined and in most of 58 patient\u2010derived myeloma cells. Treatment with <jats:styled-content style=\"fixed-case\">SGI<\/jats:styled-content>\u2010110, a hypomethylating agent, and\/or trichostatin A, a histone deacetylase inhibitor, increased miR\u2010375 expression, but repressed <jats:styled-content style=\"fixed-case\">PDPK<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1R and <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2 in <jats:styled-content style=\"fixed-case\">HMCL<\/jats:styled-content>s. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR\u2010375 repression in <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>, which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways.<\/jats:p>","DOI":"10.1111\/bjh.14707","type":"journal-article","created":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T06:13:06Z","timestamp":1493100786000},"page":"534-546","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Epigenetic repression of miR\u2010375 is the dominant mechanism for constitutive activation of the <scp>PDPK<\/scp>1\/<scp>RPS<\/scp>6<scp>KA<\/scp>3 signalling axis in multiple myeloma"],"prefix":"10.1111","volume":"178","author":[{"given":"Shotaro","family":"Tatekawa","sequence":"first","affiliation":[{"name":"Division of Haematology and Oncology 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