{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:21:33Z","timestamp":1788787293788,"version":"build-2803163510"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T00:00:00Z","timestamp":1673308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rostock University Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K\/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K\/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K\/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K\/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.<\/jats:p>","DOI":"10.3390\/ijms24021359","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T02:06:03Z","timestamp":1673402763000},"page":"1359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Combined BCL-2 and PI3K\/AKT Pathway Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9619-5380","authenticated-orcid":false,"given":"Clemens","family":"Holz","sequence":"first","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Lange","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anett","family":"Sekora","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Knuebel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Krohn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7123-7986","authenticated-orcid":false,"given":"Hugo","family":"Murua Escobar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Junghanss","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-7072","authenticated-orcid":false,"given":"Anna","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinic III\u2014Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/S0140-6736(19)33018-1","article-title":"Acute Lymphoblastic Leukaemia","volume":"395","author":"Malard","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1182\/blood-2016-03-707414","article-title":"Venetoclax Responses of Pediatric ALL Xenografts Reveal Sensitivity of MLL-Rearranged Leukemia","volume":"128","author":"Khaw","year":"2016","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41420-022-01093-3","article-title":"Effective Tumor Cell Abrogation via Venetoclax-Mediated BCL-2 Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia","volume":"8","author":"Richter","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1016\/j.celrep.2015.12.003","article-title":"MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199","volume":"13","author":"Benito","year":"2015","journal-title":"Cell Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nrd.2016.253","article-title":"From Basic Apoptosis Discoveries to Advanced Selective BCL-2 Family Inhibitors","volume":"16","author":"Ashkenazi","year":"2017","journal-title":"Nat. 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