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Familial Platelet Disorder Associated with Hematologic Malignancies

Familial platelet disorder associated with hematologic malignancies (FPDHM) is an inherited disease cause by a germline mutation in the RUNX1 gene. People with FPD are at high-risk to developing HM, primarily myelodysplastic syndromes and acute myeloid leukemia.

The mechanisms by which RUNX1 mutations cause expansion of malignant clones and HM are not well understood. Importantly, effective therapies for FPDHM are lacking. Since FPD patients can live many years in a preleukemic period, there is a unique opportunity to design FPDHM treatments.

We are interested in better understanding what molecular factors drive clonal evolution in FPD and in developing therapies that prevent or delay FPDHM.

We recently generated a mouse strain with the missense mutation R188Q in the Runx1 gene, mimicking the R201Q germline mutation found in patients with FPDHM (Ahmad et al., 2023).

The Runx1^R188Q/+ mice have features of premalignant hematopoiesis marked by

Deregulated expression of inflammatory cytokines in the bone marrow fluid.
Myeloid expansion and reduced platelet function.
Hematopoietic progenitors with reduced DNA-damage response, validating the Runx1 function in DNA integrity.
Increased long-term engraftment capacity, suggesting that gene correction therapies would require high editing efficacy.
Predispose to HM in cooperation with cooperating mutations in mice.

The Runx1^R188Q/+ mice are a valuable model for mechanistic and translational studies in FPDHM.