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Access through your institution Buy or subscribe 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]. This is

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during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support DATA AVAILABILITY Contact Julia Maxson at

[email protected] for information regarding renewable materials, datasets, and protocols. Genomic data are deposited at GEO with accession number GSE218829. REFERENCES * Tarlock K, Alonzo T,

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M-CSF receptor expressing cells. PLoS One. 2014;9:e95784. Article  PubMed  PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * 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 * Division of

Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA Theodore P. Braun & Julia E. Maxson * Cell, Developmental and Cancer Biology, Oregon

Health & Science University, Portland, OR, 97239, USA Julia E. Maxson Authors * Sarah A. Carratt View author publications You can also search for this author inPubMed Google Scholar *

Garth L. Kong View author publications You can also search for this author inPubMed Google Scholar * Cody Coblentz View author publications You can also search for this author inPubMed 

Google Scholar * Zachary Schonrock View author publications You can also search for this author inPubMed Google Scholar * Lauren Maloney View author publications You can also search for this

author inPubMed Google Scholar * Ben Weeder View author publications You can also search for this author inPubMed Google Scholar * Will Yashar View author publications You can also search

for this author inPubMed Google Scholar * Rowan Callahan View author publications You can also search for this author inPubMed Google Scholar * Hunter Blaylock View author publications You

can also search for this author inPubMed Google Scholar * Colin Coleman View author publications You can also search for this author inPubMed Google Scholar * Dan Coleman View author

publications You can also search for this author inPubMed Google Scholar * Theodore P. Braun View author publications You can also search for this author inPubMed Google Scholar * Julia E.

Maxson View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

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governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download

citation * Received: 19 December 2022 * Revised: 20 February 2023 * Accepted: 24 February 2023 * Published: 09 March 2023 * Issue Date: May 2023 * DOI:

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