2. Academic Validation
  3. PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade

PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade

  • bioRxiv. 2026 Jan 23:2026.01.20.700677. doi: 10.64898/2026.01.20.700677.
William M Yashar 1 2 3,  Itallia V Pacentine 1 2 3,  Akram Taherinasab 1 2,  Thai Nguyen 1 2,  Samantha Worme 1 2,  Mitsuhiro Tsuchiya 1 2,  Theresa Lusardi 2 4,  Chelsea Hutchinson 5,  Thomas L Fillmore 6,  Camilo Posso 5,  Sara Jc Gosline 5,  Paul D Piehowski 6,  Galip Gurkan Yardimci 2 4,  Andrew C Adey 2 5 6,  Julia E Maxson 1 2 7 8,  Theodore P Braun 1 2 7
Affiliations

Affiliations

  • 1 Division of Oncologic Sciences, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA.
  • 2 Knight Cancer Institute, Oregon Health & Science University; Portland, OR, 97239, USA.
  • 3 These authors contributed equally to this work. For CV and publication listings, both authors may designate themselves as the first author.
  • 4 Cancer Early Detection Advanced Research Center, Oregon Health & Science University; Portland, OR, 97239, USA.
  • 5 Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA.
  • 6 Environmental and Molecular Sciences Division, Pacific Northwest National Laboratory, Richland WA.
  • 7 Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University; Portland, OR, 97239, USA.
  • 8 Cell Developmental & Cancer Biology, Oregon Health & Science University; Portland, OR, 97239, USA.
PMID: 41648616 DOI: 10.64898/2026.01.20.700677
Abstract

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. Ex vivo 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.

Keywords

BCL2 inhibition; PU.1; Venetoclax; myeloid differentiation; stem-monocytic acute myeloid leukemia.

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