Inflammation and Predisposition to Familial Platelet Disorder and Hematologic Malignancies


Lucio Castilla, PhD, University of Massachusetts Medical School

Lucio Castilla, PhD

RUNX1 familial platelet disorder (RUNX1-FDP) is a rare inherited disease caused by a germline mutation in the RUNX1 gene, which encodes a transcription factor that regulates hematopoietic differentiation. Children born with a RUNX1 mutation have lifelong immune and clotting complications, and their risk of developing hematologic malignancies is 40%, which primarily presents as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Progression to MDS or AML occurs after additional somatic mutations, including the loss of the second RUNX1 allele, or mutations in components of various signal transduction pathways. Recent studies have revealed that mice with RUNX1-deficient hematopoietic stem and progenitor cells (HSPCs) have an inflammatory bone marrow, associated with the TNF/NFκB pathway, which may play a role in disease progression. However, it is not known whether inflammation regulates the emergence of clonal hematopoiesis and their expansion, and if targeting the TNF/NFκB pathway is a viable strategy to prevent AML in these patients.

Lucio Castilla and his team have generated a mouse model recapitulating a common RUNX1 mutation found in patients with RUNX1-FDP, which, like their human counterparts, are predisposed to developing hematologic malignancies. The team will treat these mice with etanercept, an inhibitor of the TNF/NFκB pathway, and monitor the effect this has on HSPC proliferation, the DNA-damage response in the mice, and their overall cytokine profile. This will establish whether the defects observed in the RUNX1-mutated HSPCs stem from aberrant signals originated in different cell types, such as the immune system, mesenchymal stroma and vascular endothelial cells. They will also observe whether treatment with etanercept reduces the overall risk to develop hematologic malignancies in the mice. These findings may serve as the foundation for the design of safe anti-inflammatory strategies in RUNX1-FPD individuals that significantly decrease their lifetime risk of developing cancer.