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Focal adhesion kinase (<jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>), regulated through calpain, interacts with molecules of <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content> signalling, cytoskeletal modelling and disease progression, such as Src\/Lyn, cortactin and <jats:styled-content style=\"fixed-case\">HS1<\/jats:styled-content>. Hypothesizing that <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content> might play a key role in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> pathogenesis, we observed a down\u2010modulation of <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content> whole form, associated with <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content> cleavage due to calpain activity upon <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content> stimulation. Patients, whose cells were able to release Ca<jats:sup>++<\/jats:sup> after <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content> stimulation, had less amount of full\u2010length <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>, which translated into a higher presence of cleaved\/activated form of the protein phosphorylated at <jats:styled-content style=\"fixed-case\">Y397<\/jats:styled-content>, these features being mostly shown by immunoglobulin heavy chain (<jats:styled-content style=\"fixed-case\">IGHV<\/jats:styled-content>)\u2010unmutated poor\u2010prognosis patients. Moreover, we found that cortactin and <jats:styled-content style=\"fixed-case\">HS1<\/jats:styled-content> proteins were overexpressed in those cells, suggesting a possible interplay with <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>. Treatment with the <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content> inhibitor Defactinib was able to induce apoptosis in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> cells. In conclusion, the malignant phenotype in unfavourable\u2010prognosis patients seems to be encouraged by the overexpression of cortactin and <jats:styled-content style=\"fixed-case\">HS1<\/jats:styled-content>, that, together with <jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>, may be involved in a druggable pathogenetic pathway in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/bjh.18996","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:45:12Z","timestamp":1690418712000},"page":"224-236","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Focal adhesion kinase activation by calcium\u2010dependent calpain is involved in chronic lymphocytic leukaemia cell aggressiveness"],"prefix":"10.1111","volume":"203","author":[{"given":"Filippo","family":"Severin","sequence":"first","affiliation":[{"name":"Hematology and 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