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MYELODYSPLASTIC NEOPLASM

RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia

Leukemia volume 37, pages 1698–1708 (2023)Cite this article

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Abstract

Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor fitness gain ectopic, dysregulated self-renewal secondary to somatic mutations via undefined mechanisms. Here, in the context of the prototypical IBMFS Fanconi anemia (FA), we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels), generating a model of IBMFS-associated MDS. We observed that compared to the failure state, FA MDS cells show mutant RUNX1-mediated blunting of the G1/S cell cycle checkpoint that is normally activated in FA in response to DNA damage. RUNX1 indels also lead to activation of innate immune signaling, which stabilizes the homologous recombination (HR) effector BRCA1, and this pathway can be targeted to abrogate viability and restore sensitivity to genotoxins in FA MDS. Together, these studies develop a paradigm for modeling clonal evolution in IBMFSs, provide basic understanding of the pathogenesis of MDS, and uncover a therapeutic target in FA-associated MDS.

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Fig. 1: Clonal evolution in FA.
Fig. 2: Diminished checkpoint activity in FA MDS.
Fig. 3: DNA damage response in FA MDS.
Fig. 4: Activation of innate inflammation in FA MDS.
Fig. 5: Targeting innate inflammation in FA MDS.

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Data availability

RNA sequencing data are available in the Gene Expression Omnibus (GSE205844) and the Database of Genotypes and Phenotypes (phs003024).

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK114527 and R01 DK134515 to R.G.R.), the Fanconi Anemia Research Fund (to R.G.R.), the Edward P. Evans Foundation (to R.G.R.), and a Leukemia & Lymphoma Society CDP fellowship (to C.C.).

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Author notes

  1. These authors contributed equally: William Marion, Tiago Koppe.

Authors and Affiliations

  1. Department of Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA

    William Marion, Tiago Koppe, Dahai Wang, Katie Frenis, Sara Fierstein, Prerana Sensharma, Olivia Aumais, Michael Peters, Akiko Shimamura, Daniel E. Bauer & R. Grant Rowe

  2. Stem Cell Program, Boston Children’s Hospital, Boston, MA, USA

    William Marion, Tiago Koppe, Dahai Wang, Katie Frenis, Sara Fierstein, Prerana Sensharma, Thorsten Schlaeger & R. Grant Rowe

  3. Massachusetts Institute of Technology, Cambridge, MA, USA

    Chun-Chin Chen

  4. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Sonya Ruiz-Torres, Tafadzwa Chihanga, Susanne I. Wells & Daniel Starczynowski

  5. Dana-Farber Cancer Institute, Boston, MA, USA

    Steffen Boettcher & Benjamin L. Ebert

  6. Department of Medical Oncology and Hematology, University of Zurich and University Hospital of Zurich, Zurich, Switzerland

    Steffen Boettcher

  7. Harvard Medical School, Boston, MA, USA

    Akiko Shimamura, Daniel E. Bauer, Benjamin L. Ebert & R. Grant Rowe

  8. Howard Hughes Medical Institute, Boston, MA, USA

    Benjamin L. Ebert

  9. University of Cincinnati Cancer Center, Cincinnati, OH, USA

    Daniel Starczynowski

  10. Federal University of Santa Catarina, Florianopolis, Brazil

    Edroaldo Lummertz da Rocha

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Contributions

W.M., T.K., C.C., D.W., K.F., S.F., P.S., O.A., T.C., S.R-T., M.P., S.B., and R.G.R. performed experiments; E.L.dR. and R.G.R. analyzed results; A.S., S.I.W., B.L.E., and D.S. provided key reagents; D.E.B. and T.S. provided key technical advice; R.G.R. designed the research and wrote the paper with feedback from S.I.W. and D.S. W.M. is leading co-first author as he executed the foundational experiments for this work.

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Correspondence to R. Grant Rowe.

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BLE has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Therapeutics, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics.

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Marion, W., Koppe, T., Chen, CC. et al. RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia. Leukemia 37, 1698–1708 (2023). https://doi.org/10.1038/s41375-023-01945-6

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