{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:29:13Z","timestamp":1787797753582,"version":"build-2784847793"},"reference-count":166,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Molecular bases of disease dissemination in lymphoid malignancies","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"Molecular bases of disease dissemination in lymphoid malignancies","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"Molecular bases of disease dissemination in lymphoid malignancies","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro Foundation","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro Foundation","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro Foundation","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]},{"name":"Progetti di Rilevante Interesse Nazionale","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"Progetti di Rilevante Interesse Nazionale","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"Progetti di Rilevante Interesse Nazionale","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]},{"name":"AGING Project\u2014Department of Excellence\u2014DIMET, Universit\u00e0 del Piemonte Orientale","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"AGING Project\u2014Department of Excellence\u2014DIMET, Universit\u00e0 del Piemonte Orientale","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"AGING Project\u2014Department of Excellence\u2014DIMET, Universit\u00e0 del Piemonte Orientale","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]},{"name":"Ricerca Finalizzata 2018","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"Ricerca Finalizzata 2018","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"Ricerca Finalizzata 2018","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]},{"name":"AIL Novara Onlus","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]},{"name":"AIL Novara Onlus","award":["2015ZMRFEA"],"award-info":[{"award-number":["2015ZMRFEA"]}]},{"name":"AIL Novara Onlus","award":["RF-2018-12365790"],"award-info":[{"award-number":["RF-2018-12365790"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27+CD45RO\u2212 CD8+ T cells.<\/jats:p>","DOI":"10.3390\/ijms241210374","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T01:35:11Z","timestamp":1687311311000},"page":"10374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9307-1965","authenticated-orcid":false,"given":"Nawar","family":"Maher","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0389-3268","authenticated-orcid":false,"given":"Samir","family":"Mouhssine","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam Francis","family":"Matti","sequence":"additional","affiliation":[{"name":"Department of Hematology and Bone Marrow Transplant, Hematology and Bone Marrow Transplant Center, Baghdad 00964, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa Fadhil","family":"Alwan","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, The National Center of Hematology, Mustansiriyah University, Baghdad 10015, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-0151","authenticated-orcid":false,"given":"Gianluca","family":"Gaidano","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"ref_1","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., and Thiele, J. 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