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We screened for misregulated <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> repair genes by enhanced <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010sequencing on bone marrow from a discovery cohort of 27 <jats:styled-content style=\"fixed-case\">CMML<\/jats:styled-content> patients and 9 controls. We validated 4 differentially expressed candidates in <jats:styled-content style=\"fixed-case\">CMML CD<\/jats:styled-content>34<jats:sup>+<\/jats:sup> bone marrow selected cells and in an independent cohort of 74 <jats:styled-content style=\"fixed-case\">CMML<\/jats:styled-content> patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases. We found <jats:italic><jats:styled-content style=\"fixed-case\">BAP<\/jats:styled-content>1<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">PARP<\/jats:styled-content>1<\/jats:italic> down\u2010regulation to be specific to <jats:styled-content style=\"fixed-case\">CMML<\/jats:styled-content> compared with other related disorders. Chromatin\u2010regulator mutated cases showed decreased <jats:italic><jats:styled-content style=\"fixed-case\">BAP<\/jats:styled-content>1<\/jats:italic> dosage. We validated a significant over\u2010expression of the double strand break\u2010fidelity genes <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>1A<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">ERCC<\/jats:styled-content>1,<\/jats:italic> independent of promoter methylation and associated with chemorefractoriness. In addition, patients bearing mutations in the splicing component <jats:italic><jats:styled-content style=\"fixed-case\">SRSF<\/jats:styled-content>2<\/jats:italic> displayed numerous aberrant splicing events in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> repair genes, with a quantitative predominance in the single strand break pathway. Our results highlight potential targets in this disease, which currently has few therapeutic options.<\/jats:p>","DOI":"10.1111\/bjh.15408","type":"journal-article","created":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T07:11:44Z","timestamp":1527145904000},"page":"373-383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Transcriptomic rationale for synthetic lethality\u2010targeting <i><scp>ERCC<\/scp>1<\/i> and <i><scp>CDKN<\/scp>1A<\/i> in chronic myelomonocytic leukaemia"],"prefix":"10.1111","volume":"182","author":[{"given":"Ana M.","family":"Hurtado","sequence":"first","affiliation":[{"name":"Haematology Department Hospital Morales Meseguer IMIB Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gines","family":"Luengo\u2010Gil","sequence":"additional","affiliation":[{"name":"Haematology Department Hospital Morales Meseguer IMIB Murcia 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