{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:06:13Z","timestamp":1760144773872,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza","doi-asserted-by":"publisher","award":["RM120172B6DF0CBB","RM12117A813AB88A"],"award-info":[{"award-number":["RM120172B6DF0CBB","RM12117A813AB88A"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]},{"name":"a philanthropic donation from Fondazione Internazionale D\u2019Amato Onlus","award":["RM120172B6DF0CBB","RM12117A813AB88A"],"award-info":[{"award-number":["RM120172B6DF0CBB","RM12117A813AB88A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical\/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy.<\/jats:p>","DOI":"10.3390\/cimb46060305","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T11:03:47Z","timestamp":1716375827000},"page":"5085-5099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition"],"prefix":"10.3390","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-4118","authenticated-orcid":false,"given":"Simone","family":"Mirabilii","sequence":"first","affiliation":[{"name":"Hematology, Department of Clinical and Molecular Medicine, Sant\u2019Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Piedimonte","sequence":"additional","affiliation":[{"name":"Hematology, Department of Clinical and Molecular Medicine, Sant\u2019Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esmeralda","family":"Conte","sequence":"additional","affiliation":[{"name":"Hematology, Department of Clinical and Molecular Medicine, Sant\u2019Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-8683","authenticated-orcid":false,"given":"Daniele","family":"Mirabilii","sequence":"additional","affiliation":[{"name":"WS Audiology, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8438-1661","authenticated-orcid":false,"given":"Francesca Maria","family":"Rossi","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8746-9404","authenticated-orcid":false,"given":"Riccardo","family":"Bomben","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-5957","authenticated-orcid":false,"given":"Antonella","family":"Zucchetto","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-9680","authenticated-orcid":false,"given":"Valter","family":"Gattei","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7911-9263","authenticated-orcid":false,"given":"Agostino","family":"Tafuri","sequence":"additional","affiliation":[{"name":"Hematology, Department of Clinical and Molecular Medicine, Sant\u2019Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8772-3521","authenticated-orcid":false,"given":"Maria Rosaria","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Hematology, Department of Clinical and Molecular Medicine, Sant\u2019Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/ajh.25595","article-title":"Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment","volume":"94","author":"Hallek","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"758","DOI":"10.3109\/10428194.2015.1106533","article-title":"Metabolism pathways in chronic lymphocytic leukemia","volume":"57","author":"Rozovski","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1158\/1541-7786.MCR-17-0026","article-title":"B cell receptor signaling regulates metabolism in Chronic Lymphocytic Leukemia","volume":"15","author":"Vangapandu","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cell.2009.08.041","article-title":"PI3 kinase signals BCR-dependent mature B cell survival","volume":"139","author":"Srinivasan","year":"2009","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12943-018-0779-z","article-title":"Role of Bruton\u2019s tyrosine kinase in B cells and malignancies","volume":"17","author":"Dammeijer","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1097\/CCO.0b013e32832f57ec","article-title":"Targeting the Warburg Effect in Hematological Malignancies: From PET to Therapy","volume":"21","author":"Shanmugan","year":"2009","journal-title":"Curr. Opin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40164-022-00292-z","article-title":"Targeting metabolic reprogramming in chronic lymphocytic leukemia","volume":"11","author":"Nie","year":"2022","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"713","DOI":"10.6004\/jnccn.2017.0081","article-title":"Chronic lymphocytic leukemia: Individualizing treatment approach","volume":"15","author":"Zelenetz","year":"2017","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1182\/blood-2013-10-532200","article-title":"Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia","volume":"123","author":"Jitschin","year":"2014","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1182\/blood-2013-11-536169","article-title":"Correlation between FDG\/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia","volume":"123","author":"Falchi","year":"2014","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.critrevonc.2018.12.003","article-title":"Metabolic rewiring beyond Warburg in chronic lymphocytic leukemia: How much do we actually know?","volume":"134","author":"Aloyz","year":"2019","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41408-017-0039-2","article-title":"Del11q-positive CLL lymphocytes exhibit altered glutamine metabolism and differential response to GLS1 and glucose metabolism inhibition","volume":"8","author":"Smith","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e722","DOI":"10.1097\/HS9.0000000000000722","article-title":"B-cell Receptor Signaling Induced Metabolic Alterations in Chronic Lymphocytic Leukemia Can Be Partially Bypassed by TP53 Abnormalities","volume":"6","author":"Kluckova","year":"2022","journal-title":"Hemasphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/bjc.2016.384","article-title":"The p53 family orchestrates the regulation of metabolism:physiological regulation and implications for cancer therapy","volume":"116","author":"Napoli","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1158\/0008-5472.CAN-03-0846","article-title":"The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression","volume":"64","author":"Armoni","year":"2004","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.leukres.2016.09.013","article-title":"TP53-induced glycolysis and apoptosis regulator protects from spontaneous apoptosis and predicts poor prognosis in chronic lymphocytic leukemia","volume":"50","author":"Hong","year":"2016","journal-title":"Leuk. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3389\/fonc.2018.00411","article-title":"Ibrutinib resistance is reduced by an inhibitor of fatty acid oxidation in primary CLL lymphocytes","volume":"8","author":"Aloyz","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.18632\/oncotarget.1508","article-title":"Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming","volume":"4","author":"Marignac","year":"2013","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1182\/blood-2014-12-617498","article-title":"Targeting the leukemia cell metabolism by the CPT1a inhibition: Functional preclinical effects in leukemias","volume":"126","author":"Ricciardi","year":"2015","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1200\/JCO.2013.50.8515","article-title":"CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia","volume":"32","author":"Bulian","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.1158\/1078-0432.CCR-21-0701","article-title":"TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia","volume":"27","author":"Bomben","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18137","DOI":"10.1038\/srep18137","article-title":"The pan-class I phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia","volume":"5","author":"Allegretti","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/B978-0-12-801415-8.00016-3","article-title":"Analysis and interpretation of microplate-based oxygen consumption and pH data","volume":"547","author":"Divakaruni","year":"2014","journal-title":"Methods Enzymol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1109\/TIT.1975.1055330","article-title":"The estimation of the gradient of a density function, with applications in pattern recognition","volume":"21","author":"Fukunaga","year":"1975","journal-title":"IEEE Trans. Inf. Theory"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1182\/blood-2016-06-719294","article-title":"Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia","volume":"129","author":"Ahn","year":"2017","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3389\/fonc.2020.00281","article-title":"Metabolic Plasticity in Chemotherapy Resistance","volume":"10","author":"Desbats","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mirabilii, S., Ricciardi, M.R., and Tafuri, A. (2020). mTOR Regulation of Metabolism in Hematologic Malignancies. Cells, 9.","DOI":"10.3390\/cells9020404"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7","DOI":"10.14302\/issn.2372-6601.jhor-13-346","article-title":"Targeting Cell Metabolism in Chronic Lymphocytic Leukaemia (CLL); Aviable Therapeutic Approach?","volume":"1","author":"Clapham","year":"2014","journal-title":"J. Hematol. Oncol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.neo.2017.07.004","article-title":"The Stromal Microenvironment Modulates Mitochondrial Oxidative Phosphorylation in Chronic Lymphocytic Leukemia Cells","volume":"19","author":"Vangapandu","year":"2017","journal-title":"Neoplasia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1182\/blood-2014-10-607036","article-title":"Stromal cell\u2013mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling","volume":"125","author":"Jitschin","year":"2015","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4598","DOI":"10.18632\/oncotarget.6727","article-title":"Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib","volume":"7","author":"Guo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3324\/haematol.2018.207399","article-title":"Another step forward in the 20-year history of IGHV mutations in chronic lymphocytic leukemia","volume":"104","year":"2019","journal-title":"Haematologica"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.3324\/haematol.2018.203067","article-title":"Energy metabolism is co-determined by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity","volume":"104","author":"Lu","year":"2019","journal-title":"Haematologica"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E306","DOI":"10.1002\/ajh.26235","article-title":"TP53 disruption as a risk factor in the era of targeted therapies: A multicenter retrospective study of 525 chronic lymphocytic leukemia cases","volume":"96","author":"Morabito","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s41375-023-01845-9","article-title":"Clinical impact of TP53 disruption in chronic lymphocytic leukemia patients treated with ibrutinib: A campus CLL study","volume":"37","author":"Bomben","year":"2023","journal-title":"Leukemia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00328-17","DOI":"10.1128\/MCB.00328-17","article-title":"Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism","volume":"37","author":"Eriksson","year":"2017","journal-title":"Mol. Cell. Biol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/6\/305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:46:39Z","timestamp":1760107599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/6\/305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,22]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["cimb46060305"],"URL":"https:\/\/doi.org\/10.3390\/cimb46060305","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2024,5,22]]}}}