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In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or <jats:italic><jats:styled-content style=\"fixed-case\">IGVH<\/jats:styled-content><\/jats:italic> mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> cells, such as <jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>3, <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB, p38, <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">RAF<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>. Dinaciclib was also able to block the expression of anti\u2010apoptotic proteins of the <jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>2 family such as <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">xL<\/jats:styled-content> (also termed <jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>2L1). Finally, we showed that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and the <jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>2 inhibitor <jats:styled-content style=\"fixed-case\">ABT<\/jats:styled-content>\u2010199, two drugs with known effects on <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content>. Taken together, our data show that dinaciclib targets multiple pro\u2010survival signalling pathways in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content>, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin\u2010dependent kinase inhibitors in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> in combination with other relevant targeted therapies.<\/jats:p>","DOI":"10.1111\/bjh.14285","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T22:14:44Z","timestamp":1479334484000},"page":"641-651","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Pro\u2010survival signal inhibition by <scp>CDK<\/scp> inhibitor dinaciclib in Chronic Lymphocytic Leukaemia"],"prefix":"10.1111","volume":"175","author":[{"given":"Yixiang","family":"Chen","sequence":"first","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Germano","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Clements","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesvin","family":"Samuel","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghalia","family":"Shelmani","sequence":"additional","affiliation":[{"name":"Mechanisms of Cancer and Ageing Laboratory Department of Molecular and Cell Biology University of Leicester Leicester UK"},{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Jayne","sequence":"additional","affiliation":[{"name":"Ernest and Helen Scott Haematological Research Institute University of Leicester Leicester UK"},{"name":"Department of Cancer Studies University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J. 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