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

Abstract

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 (Runx1 L148A/− mice), which display many hematologic characteristics found in human RUNX1-FPD patients. Runx1 L148A/− 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;Runx1 fl/fl mice 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.

Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice

“…In addition, this analysis reveals that Runx1 R188Q/+ HSPCs have selective expansion in both genetic backgrounds, albeit the differences seen in HSPC compartment, indicating that nonhematopoietic cells have negligible impact on the long-term expansion of Runx1-mutant HSPCs. Interestingly, Runx1-loss in BM mesenchymal stem cells, which secrete cytokines and chemokines in the BM, did not affect HSC function, 50 arguing that the source of BM inflammation may reside in the Runx1 R188Q/+ HSC–derived hematopoietic progenitors and immune cells.…”