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ACUTE MYELOID LEUKEMIA

RUNX1::ETO translocations must precede CSF3R mutations to promote acute myeloid leukemia development

Leukemia volume 37, pages 1141–1146 (2023)Cite this article

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Acute myeloid leukemia (AML) is a deadly blood cancer characterized by an overproduction of immature myeloid cells. AML has a high degree of genetic diversity, and the presence or absence of particular genetic alterations can greatly impact prognosis. One such prognosis-altering mutation is in Colony Stimulating Factor 3 Receptor (CSF3R, aka the G-CSF receptor). In pediatric AML, patients with CSF3R mutations exhibit high relapse rates [1]. Similarly, in CSF3R-mutant adult AML, the 5-year overall survival rate is a dismal 17% [2].

The role of CSF3R in normal hematopoiesis is to induce a signaling cascade that results in the production of mature neutrophils. Constitutively activating mutations in CSF3R can drive chronic neutrophilic leukemia, a myeloproliferative neoplasm characterized by an abundance of mature neutrophils [3]. However, in the presence of a mutation that blocks myeloid differentiation, CSF3R mutations can also cause AML [4,5,6]. A recent study found that 90.5% of patients with CSF3R mutations had co-occurring RUNX1::ETO (8;21), CBFB::MYH11, or CEBPA mutations [4]. The RUNX1::ETO and CBFB::MYH11 translocations disrupt the core binding factor complex, an important transcriptional regulator of myeloid development [7]. Similarly, mutations in the transcription factor CEBPA impair differentiation to transform the myeloid lineage [8]. In prior studies, we found that mutations in CEBPA block the ability of CSF3R to activate myeloid lineage enhancers without impairing CSF3R-driven proliferation programs [9]. This results in the expansion of myeloblasts that characterizes AML [9].

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Fig. 1: RUNX1::ETO and CSF3RT618I synergize to drive increased proliferation in vitro and in vivo in an order-dependent manner.
Fig. 2: RUNX1::ETO impairs CSF3RT618I-driven myeloid differentiation, especially when expressed first.

Data availability

Contact Julia Maxson at maxsonj@ohsu.edu for information regarding renewable materials, datasets, and protocols. Genomic data are deposited at GEO with accession number GSE218829.

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Acknowledgements

Research reported in this publication was supported by NCI F32CA239422 and an OHSU SciOps award to SAC; an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award and 1 K08 CA245224 from NCI awarded to TPB; NCI R01 CA247943, American Cancer Society RSG-19-184-01-LIB, and an LLS Scholar Award to JEM. We thank the following OHSU core facilities for their assistance: Advanced Light Microscopy, Histopathology Shared Resource, Flow Cytometry Shared Resource, ExaCloud Cluster Computational Resource, and the Advanced Computing Center.

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Authors and Affiliations

  1. Division of Oncologic Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA

    Sarah A. Carratt, Garth L. Kong, Cody Coblentz, Zachary Schonrock, Lauren Maloney, Ben Weeder, Will Yashar, Rowan Callahan, Hunter Blaylock, Colin Coleman, Dan Coleman, Theodore P. Braun & Julia E. Maxson

  2. Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA

    Theodore P. Braun & Julia E. Maxson

  3. Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA

    Julia E. Maxson

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  1. Sarah A. Carratt
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Contributions

Concept and design: SAC, TPB, JEM. In vitro experiments: SAC, LM, HB, C. Coleman, DC, TPB, JEM. In vivo experiments: SAC, C Coblentz, ZS, TPB. Computational resources and analysis: GLK, BW, WY, RC, TPB. Analysis and interpretation of data: all authors. Writing, review and revision of the manuscript: all authors.

Corresponding authors

Correspondence to Theodore P. Braun or Julia E. Maxson.

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Competing interests

JEM discloses a collaboration with Ionis pharmaceuticals, research funding from Gilead Sciences, Kura Oncology and Blueprint Medicines. WY is a former employee of Abreos Biosciences, Inc. and was compensated in part with common stock options. Pursuant to the merger and reorganization agreement between Abreos Biosciences, Inc. and Fimafeng, Inc., WY surrendered all of his common stock options in March 2021. The other authors do not have conflicts of interest, financial or otherwise.

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Carratt, S.A., Kong, G.L., Coblentz, C. et al. RUNX1::ETO translocations must precede CSF3R mutations to promote acute myeloid leukemia development. Leukemia 37, 1141–1146 (2023). https://doi.org/10.1038/s41375-023-01862-8

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