{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T08:00:34Z","timestamp":1778572834948,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Servier Pharmaceuticals","award":["CCT 2020-13856"],"award-info":[{"award-number":["CCT 2020-13856"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA). We report that CalPegA enhances the anti-leukemic effect of S55746 but does not impact the activity of S63845. The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E\/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.<\/jats:p>","DOI":"10.3390\/ijms252313091","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T08:33:51Z","timestamp":1733387631000},"page":"13091","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"25","author":[{"given":"Dominique","family":"Bollino","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"},{"name":"Department of Medical Oncology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinrong","family":"Ma","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla M.","family":"Tighe","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Casildo","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Richard","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"},{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonino","family":"Passaniti","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"},{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon","family":"Carter-Cooper","sequence":"additional","affiliation":[{"name":"The Biology Department, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin T.","family":"Strovel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3769-3210","authenticated-orcid":false,"given":"Ashkan","family":"Emadi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"},{"name":"Department of Medical Oncology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1182\/blood-2011-04-347849","article-title":"Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets","volume":"118","author":"Schoenwaelder","year":"2011","journal-title":"Blood"},{"key":"ref_2","unstructured":"FDA (2024, September 10). 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