Clinical and translational studies of RUNX1 and FPDMM

RUNX1的种系突变导致家族性血小板疾病伴髓系恶性肿瘤（FPDMM），这是一种罕见的常染色体显性遗传病。患有这种疾病的患者有巨核细胞发育缺陷，血小板计数低，血小板功能缺陷，导致凝血缺陷，并易患血液系统恶性肿瘤。FPDMM患者具有终身造血恶性肿瘤的风险，具有不同RUNX1种系突变的家族之间的临床表现和疾病外显率不同，甚至在具有相同RUNX1突变的单个家族中的受影响个体之间也是如此。目前还没有好的生物标志物或简单的检测方法来预测疾病的结果，患者需要频繁的办公室就诊和侵入性手术，如骨髓活检来监测他们的疾病进展。许多FPD患者没有发生白血病的事实表明，RUNX1突变本身并不足以导致白血病的发生；在克隆进化之后还需要额外的体细胞突变。

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.