Runx1-R188Q germline mutation induces inflammation and predisposition to hematologic malignancies in mice.

Germline mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). FPD patients frequently show clonal expansion of pre-malignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the pre-malignant bone marrow is not well understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the bone marrow. Furthermore, the expression of CD48, another inflammation response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, utilizing three mouse models. These studies establish a novel murine FPDHM model and demonstrate that germline Runx1 mutations induce a pre-malignant phenotype marked by bone marrow inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.