Clinical and translational studies of RUNX1 and FPDMM

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Germline mutations in RUNX1 cause familial platelet disorder with associated myeloid malignancies (FPDMM), a rare autosomal dominant disease. Patients with this disorder have defective megakaryocytic development, low platelet count and defective platelet functions that lead to clotting defects, and predisposition of the patients for hematological malignancies. FPDMM patients have a life-long risk of hematopoietic malignancies, with variable clinical presentation and disease penetrance among families with different RUNX1 germline mutations, and even between affected individuals within a single family who have the same RUNX1 mutation. Currently there are no good biomarkers or easy assays to predict disease outcome, and the patients need to have frequent office visits and invasive procedures such as bone marrow biopsy to monitor their disease progression. The fact that many FPD patients do not develop leukemia suggest that RUNX1 mutation by itself is not sufficient for leukemogenesis; additional somatic mutations followed by clonal evolution are needed. To address these issues for better understanding of the clinical course and underlying pathogenic mechanism of FPDMM, we launched a natural history study of FPDMM at the NIH Clinical Center in early 2019. https://clinicaltrials.gov/ct2/show/NCT03854318 https://clinicalstudies.info.nih.gov/ProtocolDetails.aspx?A_19-HG-0059.html%20InternalRUNX1 The goals of the natural history study are to identify and follow patients with FPDMM with the hope of identifying biomarkers that can predict which patients will progress and develop malignancies and to identify secondary gene mutations that may impact clinical presentation, disease severity, and progression to malignancies. Through our study we hope to determine genotype-phenotype correlations for RUNX1 mutations and validate the importance of 2nd hits that cooperate with RUNX1 germline mutations for leukemogenesis. And we desire to comprehensively phenotype the patients to determine the full spectrum of the manifestations of the germline RUNX1 mutations. We have published two papers, reporting the clinical and genomic findings, respectively, from our longitudinal natural history study of patients with germline RUNX1 variants and FPDMM, based on data collected in the first three years (Cunningham et al., 2023; Yu et al., 2024). The first provided a comprehensive report of clinical phenotypes of FPDMM, while the second provided a detailed description of the genomic data, focusing on the type and frequency of somatic mutations in CHIP (clonal hematopoiesis with indetermined potential) and leukemia genes. In collaboration with Dr. Anupriya Argawal at Oregon Health Science University, we published results highlighting that inflammation is an early event in FPDMM pathogenesis and CD74 signaling is one of the drivers of this inflammation (Mohammadhosseini et al, 2025). At least 38 FPDMM patients in our study have been pregnant; and we recently analyzed the outcomes of these pregnancies and deliveries (Deuitch et al, 2025). Genetic testing to identify hereditary predispositions to hematologic malignancies is critical prior to allogenic hematopoietic cell transplantation, particularly regarding implications for using a related donor. We recently published a short paper reviewing three cases in our natural history study cohort, which highlight this point (Kajdic et al., 2025).