{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:54:50Z","timestamp":1785430490409,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Cancer Biology","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R00CA252005"],"award-info":[{"award-number":["R00CA252005"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R00CA248460"],"award-info":[{"award-number":["R00CA248460"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Junior Faculty Scholar Award (L.A.M, R.L.B)"],"award-info":[{"award-number":["Junior Faculty Scholar Award (L.A.M, R.L.B)"]}],"id":[{"id":"https:\/\/ror.org\/02nw48b86","id-type":"ROR","asserted-by":"publisher"}]},{"award":["IRG-23-1141524-01-IRG"],"award-info":[{"award-number":["IRG-23-1141524-01-IRG"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012875","name":"University of Cincinnati Cancer Center","doi-asserted-by":"crossref","award":["Pilot Award (L.A.M.)"],"award-info":[{"award-number":["Pilot Award (L.A.M.)"]}],"id":[{"id":"10.13039\/100012875","id-type":"DOI","asserted-by":"crossref"}]},{"award":["College of Medicine Carey & Stella Wamsley Charitable Trust"],"award-info":[{"award-number":["College of Medicine Carey & Stella Wamsley Charitable Trust"]}],"id":[{"id":"https:\/\/ror.org\/01e3m7079","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the RAS\/MAPK signaling pathway are recurrent in acute myeloid leukemia (AML), primarily involving\n                  <jats:italic>NRAS<\/jats:italic>\n                  and\n                  <jats:italic>KRAS<\/jats:italic>\n                  . In contrast, mutations in the gene encoding an effector protein, BRAF, occur at relatively lower frequencies in AML and are associated with poor outcomes. To date, no comprehensive analysis has assessed the clinical and molecular characteristics of\n                  <jats:italic>BRAF-<\/jats:italic>\n                  mutated AML. In this study, we report the identification of canonical and non-canonical\n                  <jats:italic>BRAF<\/jats:italic>\n                  mutations in \u223c1% of 5,779 consecutive clinically and molecularly fully-annotated AML patients treated at two major United States Cancer Centers (50\/5779 AML patients: 21 newly diagnosed AML; 9 relapsed\/refractory; 20 newly diagnosed secondary AML). We performed single-cell multiomic analysis on a subset of AML samples.\n                  <jats:italic>BRAF<\/jats:italic>\n                  mutations were enriched in myelodysplasia-related AML (AML-MR), and most mutations were located outside the V600 hotspot. Single-cell multiomic profiling delineated\n                  <jats:italic>BRAF<\/jats:italic>\n                  mutation class-specific patterns of co-mutations, clonality, and immunophenotypes. Notably,\n                  <jats:italic>BRAF<\/jats:italic>\n                  mutations and other signaling co-mutation(s) could be found in the same cell, a finding that significantly diverges from prior studies of RAS-mutant AML. In this cohort,\n                  <jats:italic>BRAF<\/jats:italic>\n                  -mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of\n                  <jats:italic>BRAF<\/jats:italic>\n                  -mutated AML.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>\n                    Canonical and non-canonical\n                    <jats:italic>BRAF<\/jats:italic>\n                    mutations are enriched in AML-MR and associate with poor survival outcomes. Single-cell multiomic profiling revealed unique co-mutation patterns and immunophenotypes that highlight RAS pathway addiction and nominate\n                    <jats:italic>BRAF<\/jats:italic>\n                    -mutated disease as a distinct subtype within RAS pathway-aberrated leukemias. Drug sensitivity screens suggest broad CDK or HSP90 inhibition in addition to BRAF\/RAS-directed inhibition may be effective targeted therapies in this prognostically poor AML subtype.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.14.682328","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T22:10:14Z","timestamp":1760566214000},"source":"Crossref","is-referenced-by-count":0,"title":["Prognostic and Therapeutic Implications of\n                  <i>BRAF<\/i>\n                  Mutations in Acute Myeloid Leukemia"],"prefix":"10.64898","author":[{"given":"Darren","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazan","family":"Abu-Shihab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Plas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deedra","family":"Nicolet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Mrozek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Routbort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyur P.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Buss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Stiff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Laganson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney D.","family":"DiNardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naval G.","family":"Daver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-9832","authenticated-orcid":false,"given":"Tapan M.","family":"Kadia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhad","family":"Ravandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Kolitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayard L.","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Baer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey L.","family":"Uy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Stock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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