Clinical and translational studies of RUNX1 and FPDMM

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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. By August 15, 2023, we have enrolled 217 participants in our natural history study. We had 55 participants who visited NIH Clinical Center (CC) for their annual checkups during the last year. In addition, we received remote patient samples (blood and bone marrow) from patients who could not travel to NIH and had procedures locally. For patients who visited NIH CC, we performed clinical examinations and lab tests to document clinical manifestations associated with FPDMM, including those outside of the hematopoietic system. We collected peripheral blood and bone marrow samples for hematological, immunological, and histological examinations and tests. With the biological samples, both collected at NIH CC and received remotely, we have been performing genomic analysis to determine germline and somatic changes in the hematopoietic cells in the participants. We are also performing functional and translational studies to determine the functional consequences of the detected RUNX1 variants in our patients, with both bench research tools as well as model systems including cell lines derived from patient samples and animal models such as the zebrafish and mouse. We have submitted manuscripts reporting the initial findings from our clinical and genomic studies, which are under peer-review by scientific journals for publication.