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The predominant form of proteasome in these hematologic malignancies is the lymphoid tissue-specific immunoproteasome. FDA-approved PIs inhibit immunoproteasomes and ubiquitously expressed constitutive proteasomes causing on-target toxicities in non-hematological tissues. Replacing PIs with selective immunoproteasome inhibitors (IPIs) should reduce these toxicities. We have previously shown that IPI ONX-0914 causes apoptosis of ALL cells expressing the KMT2A::AFF1 (MLL-AF4) fusion protein but did not elucidate the mechanism. Here we show that a novel, highly specific IPI M3258 induces rapid apoptosis in ALL cells in vitro and is comparable to bortezomib in its ability to reduce tumor growth and to cause tumor regression when combined with chemotherapy in vivo. Treatment of KMT2A::AFF1 ALL cells with M3258, ONX-0914, and bortezomib induced proteotoxic stress that was prevented by the protein synthesis inhibitor cycloheximide, which dramatically desensitized cells to PI-induced apoptosis. Thus, similar to multiple myeloma, ALL cells are sensitive to PIs and IPIs due to increased proteotoxic stress caused by elevated rates of protein synthesis.<\/jats:p>","DOI":"10.1038\/s41598-025-01657-0","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T01:30:03Z","timestamp":1747618203000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Highly specific Immunoproteasome inhibitor M3258 induces proteotoxic stress and apoptosis in KMT2A::AFF1 driven acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"15","author":[{"given":"Tyler W.","family":"Jenkins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn Elise","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addison M.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy L.","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith S.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid A.","family":"Houry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey V.","family":"Maksimenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Panizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia Y.","family":"Maxuitenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew Shane","family":"Loop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit K.","family":"Mitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei F.","family":"Kisselev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"1657_CR1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1182\/blood-2012-04-418640","volume":"120","author":"YH Messinger","year":"2012","unstructured":"Messinger, Y. 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