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The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL\u2013AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL\u2013AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (\u00df5i) and LMP2 (\u00df1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome \u00df2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL.<\/jats:p>","DOI":"10.1038\/s41598-021-90451-9","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T10:03:15Z","timestamp":1621936995000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL\u2013AF4 fusion protein"],"prefix":"10.1038","volume":"11","author":[{"given":"Tyler W.","family":"Jenkins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sondra L.","family":"Downey-Kopyscinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Fields","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert J.","family":"Rahme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Colley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Israel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey V.","family":"Maksimenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven N.","family":"Fiering","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":[[2021,5,25]]},"reference":[{"key":"90451_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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