Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1 -FPD

Martijn P.T. Ernst, Eline Pronk, Claire Van Dijk, Paulina M.H. Van Strien, Tim V.D. Van Tienhoven, Michiel J.W. Wevers, Mathijs A. Sanders, Eric M.J. Bindels, Nancy A. Speck, Marc H.G.P. Raaijmakers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
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RUNX1 familial platelet disorder (RUNX1-FPD) is a hematopoietic disorder caused by germline loss-of-function mutations in the RUNX1 gene and characterized by thrombocytopathy, thrombocytopenia, and an increased risk of developing hematologic malignancies, mostly of myeloid origin. Disease pathophysiology has remained incompletely understood, in part because of a shortage of in vivo models recapitulating the germline RUNX1 loss of function found in humans, precluding the study of potential contributions of non-hematopoietic cells to disease pathogenesis. Here, we studied mice harboring a germline hypomorphic mutation of one Runx1 allele with a loss-of-function mutation in the other Runx1 allele (Runx1L148A/-mice), which display many hematologic characteristics found in human RUNX1-FPD patients. Runx1L148A/-mice displayed robust and pronounced thrombocytopenia and myeloid-biased hematopoiesis, associated with an HSC intrinsic reconstitution defect in lymphopoiesis and expansion of myeloid progenitor cell pools. We demonstrate that specific deletion of Runx1 from bone marrow stromal cells in Prrx1-cre;Runx1fl/flmice did not recapitulate these abnormalities, indicating that the hematopoietic abnormalities are intrinsic to the hematopoietic lineage, and arguing against a driving role of the bone marrow microenvironment. In conclusion, we report a RUNX1-FPD mouse model faithfully recapitulating key characteristics of human disease. Findings do not support a driving role of ancillary, non-hematopoietic cells in the disruption of hematopoiesis under homeostatic conditions.

Original languageEnglish
Article numberE824
Issue number2
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
This work was supported by Alex’s Lemonade Stand Foundation for Childhood Cancer-Familial RUNX1 Research Grant to MHGPR.

Publisher Copyright:
© 2023 Wolters Kluwer Health. All rights reserved.


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