{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:04:32Z","timestamp":1790787872453,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria-ER contact sites (MERCS) that restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX\/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein-protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.<\/jats:p>","DOI":"10.1182\/blood.2026033874","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:02:47Z","timestamp":1788976967000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-2432","authenticated-orcid":false,"given":"Thomas E.","family":"Lew","sequence":"first","affiliation":[{"name":"The Royal Melbourne Hospital and Peter MacCallum Cancer Centre;Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3866-4318","authenticated-orcid":false,"given":"Mark F","family":"van Delft","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-6553","authenticated-orcid":false,"given":"Luuk","family":"Heitink","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9927-8998","authenticated-orcid":false,"given":"Simon A","family":"Cobbold","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine Anne","family":"White","sequence":"additional","affiliation":[{"name":"oNKo-Innate, Melbourne, Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0636-7894","authenticated-orcid":false,"given":"Jason Alfredo Randall","family":"Bong","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8692-9413","authenticated-orcid":false,"given":"Philip","family":"Hittmeyer","sequence":"additional","affiliation":[{"name":"University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5817-9450","authenticated-orcid":false,"given":"Amelia H","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet","family":"Vaibhav","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2364-6299","authenticated-orcid":false,"given":"Jumana","family":"Yousef","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4171-3712","authenticated-orcid":false,"given":"Laura F","family":"Dagley","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D","family":"Riffkin","sequence":"additional","affiliation":[{"name":"Walter and Elisa Hall Institute, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Georgiou","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Hilton","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2542-1616","authenticated-orcid":false,"given":"Allan Shuai","family":"Huang","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9353-1702","authenticated-orcid":false,"given":"Yin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Princess Alexandra Hospital, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miles B","family":"Horton","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5464-5029","authenticated-orcid":false,"given":"Mark A.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7341-5720","authenticated-orcid":false,"given":"Andrew W","family":"Roberts","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-4873","authenticated-orcid":false,"given":"David Ching Siang","family":"Huang","sequence":"additional","affiliation":[{"name":"The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,9]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033874\/2588238\/blood.2026033874.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033874\/2588238\/blood.2026033874.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:45:17Z","timestamp":1790786717000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026033874\/570870\/The-stress-sensing-MARCH5-axis-governs-blood"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026033874","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"article-number":"blood.2026033874"}}