{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:34Z","timestamp":1792790374790,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Cancer Biology","reference-count":85,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Hope Funds for Cancer Research","id":[{"id":"https:\/\/ror.org\/02s0c9732","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wipe Out Kids\u2019 Cancer Foundation"},{"name":"National Institutes of Health","award":["K99 CA293268"],"award-info":[{"award-number":["K99 CA293268"]}]},{"name":"National Institutes of Health","award":["R35 CA232105"],"award-info":[{"award-number":["R35 CA232105"]}]},{"name":"National Institutes of Health","award":["R01 GM132129"],"award-info":[{"award-number":["R01 GM132129"]}]},{"name":"National Institutes of Health","award":["P01 HL131477"],"award-info":[{"award-number":["P01 HL131477"]}]},{"name":"Harvard Ludwig Cancer Center"},{"name":"FIS","award":["FIS-2024-06156 project"],"award-info":[{"award-number":["FIS-2024-06156 project"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cancer genes are classically categorized as oncogenes or tumor suppressors based on whether gain or loss of function promotes malignancy. Here we show that oncogene-imposed dosage constraints can produce mutations that mimic tumor suppressor loss yet mark essential genes. In acute promyelocytic leukemia (APL), the transcription factor\n                  <jats:italic>EBF3<\/jats:italic>\n                  gene harbors recurrent heterozygous loss-of-function mutations, a tumor suppressor signature, and is essential for APL survival. We resolve this paradox by showing that while PML::RARA, the fusion oncoprotein defining APL, drives EBF3 expression, excess EBF3 suppresses proliferation. Patient mutations reduce EBF3 activity through heterozygous inactivation, optimizing its expression within a corridor bounded by fitness constraints at both extremes. PML::RARA activates\n                  <jats:italic>EBF3<\/jats:italic>\n                  via a p300-dependent intronic enhancer, and p300 inhibition exploits this constraint by suppressing EBF3 below the viability threshold. Our findings reveal that oncogenes can impose dosage constraints that drive adaptive mutations conventionally misclassified as tumor suppressor loss, with implications for interpreting cancer genomes.\n                <\/jats:p>","DOI":"10.64898\/2026.09.29.755484","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:30:25Z","timestamp":1790789425000},"source":"Crossref","is-referenced-by-count":0,"title":["Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia"],"prefix":"10.64898","author":[{"given":"Jonathan D.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison M.","family":"Uyemura","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"},{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Lamini","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan R.","family":"Posey","sequence":"additional","affiliation":[{"name":"Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie H.","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amyah C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Massachusetts General 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USA"},{"name":"Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao A.","family":"Paulo","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Tenen","sequence":"additional","affiliation":[{"name":"Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Clohessy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Voso","sequence":"additional","affiliation":[{"name":"Tor Vergata University, Department of Biomedicine and Prevention, Rome, 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