{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:46:50Z","timestamp":1770335210793,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,23]]},"group-title":"Cancer Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["1F30CA278500-01A1"],"award-info":[{"award-number":["1F30CA278500-01A1"]}]},{"name":"National Cancer Institute","award":["K08 CA245224"],"award-info":[{"award-number":["K08 CA245224"]}]},{"name":"National Cancer Institute","award":["1R01 CA282133-01"],"award-info":[{"award-number":["1R01 CA282133-01"]}]},{"name":"National Cancer Institute","award":["R01CA247943"],"award-info":[{"award-number":["R01CA247943"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["P30 CA016672-40"],"award-info":[{"award-number":["P30 CA016672-40"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"crossref","award":["American Society of Hematology Research Restart and Scholar Award"],"award-info":[{"award-number":["American Society of Hematology Research Restart and Scholar Award"]}],"id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000043","name":"American Association For Cancer Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Acute myeloid leukemia (AML) exhibits substantial transcriptional heterogeneity across differentiation states that influences therapeutic response to BCL2 inhibition with venetoclax. While hematopoietic stem cell (HSC)-like AMLs show high sensitivity to venetoclax and monocytic-like AMLs demonstrate resistance, the therapeutic behavior of leukemias harboring both transcriptional programs remains poorly defined. Analysis of a large AML cohort reveals a distinct patient population exhibiting concurrent HSC- and monocyte-like transcriptional signatures, which we term stem-monocytic AML.\n                  <jats:italic>Ex vivo<\/jats:italic>\n                  drug sensitivity profiling demonstrates that stem-monocytic AMLs exhibit venetoclax resistance comparable to pure monocytic disease, despite expressing HSC-like transcriptional features. Using a leukemia cell line model that recapitulates stem-monocytic AML characteristics, we show through immunophenotyping and single-cell lineage tracing that venetoclax preferentially depletes immature blasts while sparing differentiated monocytic populations. Single-cell transcriptomic and chromatin accessibility analyses identify enrichment of myeloid differentiation transcription factors, particularly PU.1, in resistant populations. A targeted CRISPR knockout screen confirms that PU.1 disruption induces differentiation arrest and enhances venetoclax sensitivity primarily in the immature immunophenotypic compartments. Pharmacologic PU.1 inhibition with the small molecule DB2313 synergizes with venetoclax in both cell line models and primary patient samples. These findings establish stem-monocytic AML as a transcriptionally and functionally distinct subtype and nominate combined PU.1 and BCL2 inhibition as a rational therapeutic strategy for improving venetoclax response in this patient population.\n                <\/jats:p>","DOI":"10.64898\/2026.01.20.700677","type":"posted-content","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T20:35:12Z","timestamp":1769200512000},"source":"Crossref","is-referenced-by-count":0,"title":["PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-9850","authenticated-orcid":false,"given":"William M","family":"Yashar","sequence":"first","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itallia V","family":"Pacentine","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akram","family":"Taherinasab","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thai","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Worme","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiro","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"Lusardi","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA"},{"name":"Cancer Early Detection Advanced Research Center, Oregon Health & Science University; Portland, OR, 97239, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chelsea","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas L","family":"Fillmore","sequence":"additional","affiliation":[{"name":"Environmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilo","family":"Posso","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara JC","family":"Gosline","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul D","family":"Piehowski","sequence":"additional","affiliation":[{"name":"Environmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland WA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galip Gurkan","family":"Yardimci","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University; 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