Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.


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

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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 for information regarding renewable materials, datasets, and protocols. Genomic data are deposited at GEO with accession number GSE218829.


  1. Tarlock K, Alonzo T, Wang YC, Gerbing RB, Ries RE, Hylkema T, et al. Prognostic impact of CSF3R mutations in favorable risk childhood acute myeloid leukemia. Blood. 2020;135:1603–6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Su L, Gao S, Tan Y, Lin H, Liu X, Liu S, et al. CSF3R mutations were associated with an unfavorable prognosis in patients with acute myeloid leukemia with CEBPA double mutations. Ann Hematol. 2019;98:1641–6.

    Article  CAS  PubMed  Google Scholar 

  3. Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368:1781–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Wang F, Chen X, Zhang Y, Wang M, Liu H, et al. CSF3R mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer. 2018;124:3329–38.

    Article  CAS  PubMed  Google Scholar 

  5. Sano H, Ohki K, Park MJ, Shiba N, Hara Y, Sotomatsu M, et al. CSF3R and CALR mutations in paediatric myeloid disorders and the association of CSF3R mutations with translocations, including t(8; 21). Br J Haematol. 2015;170:391–7.

    Article  CAS  PubMed  Google Scholar 

  6. Maxson JE, Ries RE, Wang YC, Gerbing RB, Kolb EA, Thompson SL, et al. CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood. 2016;127:3094–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2:502–13.

    Article  CAS  PubMed  Google Scholar 

  8. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;27:263–70.

    Article  CAS  PubMed  Google Scholar 

  9. Braun TP, Okhovat M, Coblentz C, Carratt SA, Foley A, Schonrock Z, et al. Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia. Nat Commun. 2019;10:5455.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002;99:3801–5.

    Article  CAS  PubMed  Google Scholar 

  11. Kohzaki H, Ito K, Huang G, Wee HJ, Murakami Y, Ito Y. Block of granulocytic differentiation of 32Dcl3 cells by AML1/ETO(MTG8) but not by highly expressed Bcl-2. Oncogene. 1999;18:4055–62.

    Article  CAS  PubMed  Google Scholar 

  12. Metcalf D, Nicola NA. Proliferative effects of purified granulocyte colony-stimulating factor (G-CSF) on normal mouse hemopoietic cells. J Cell Physiol. 1983;116:198–206.

    Article  CAS  PubMed  Google Scholar 

  13. Wang GG, Calvo KR, Pasillas MP, Sykes DB, Hacker H, Kamps MP. Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nat Methods. 2006;3:287–93.

    Article  CAS  PubMed  Google Scholar 

  14. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015;12:453–7.

  15. Su L, Tan Y, Lin H, Liu X, Yu L, Yang Y, et al. Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance. Oncotarget. 2018;9:24970–9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Guo H, Ma O, Speck NA, Friedman AD. Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood. 2012;119:4408–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang W, Wang X, Ward AC, Touw IP, Friedman AD. C/EBPalpha and G-CSF receptor signals cooperate to induce the myeloperoxidase and neutrophil elastase genes. Leukemia. 2001;15:779–86.

    Article  CAS  PubMed  Google Scholar 

  18. Ma O, Hong S, Guo H, Ghiaur G, Friedman AD. Granulopoiesis requires increased C/EBPalpha compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells. PLoS One. 2014;9:e95784.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


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



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 published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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 (2023).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links