Clinical and translational studies of RUNX1 and FPDMM

RUNX1 和 FPDMM 的临床和转化研究

• 批准号: 10700696
• 负责人: Paul Liu
• 金额: $ 163.3万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700696
• 关键词: Address; Affect; Animal Model; Biological; Biological Assay; Biological Markers; Biological Models; Bleeding time procedure; Blood; Blood Cells; Bone Marrow; Bone marrow biopsy; CBFB gene; Cell Line; Cells; Clinical; Clinical Research; Clonal Evolution; Coagulation Process; Communities; Consultations; Data; Databases; Defect; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Educational process of instructing; Enrollment; Familial Platelet Disorder; Family; Gene Expression; Gene Mutation; Genetic; Genomic approach; Genomics; Genotype; Germ-Line Mutation; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Histologic; Immunologics; Individual; Innovative Therapy; Journals; Knowledge; Laboratory Research; Lead; Life; Malignant - descriptor; Malignant Neoplasms; Medical; Molecular; Monitor; Mus; Mutation; Myeloproliferative disease; Natural History; Office Visits; Participant; Pathogenesis; Pathogenicity; Patients; Peer Review; Penetrance; Phenotype; Platelet Count measurement; Predisposition; Procedures; Process; Publishing; RUNX1 gene; Rare Diseases; Research; Risk; Sample Size; Sampling; Severity of illness; Somatic Mutation; Specialist; Syndrome; Techniques; Technology; Testing; Transgenic Animals; United States National Institutes of Health; Variant; Visit; Work; Zebrafish; checkup examination; clinical center; clinical examination; epigenomics; experience; fusion gene; genetic approach; genomic tools; hematopoietic tissue; leukemia; leukemogenesis; mutant; peripheral blood; platelet function; telehealth; tool; translational study; tumorigenesis

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. From July 2021 to July 2022, we enrolled 101 participants in our natural history study. We had 55 participants who visited NIH Clinical Center (CC) for their annual checkups during the same period. In addition, we have performed telehealth sessions with patients who could not travel to NIH and received remote patient samples (blood and bone marrow) from patients who 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. Our data will be made available to the research community soon, both as research articles published in peer-reviewed journals and as deidentified databases accessible to the research community.

RUNX 1的生殖系突变导致家族性血小板疾病伴相关骨髓恶性肿瘤（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具有缺陷的巨核细胞发育、低血小板计数和导致凝血缺陷的缺陷的血小板功能，以及患者对血液恶性肿瘤的易感性。FPDMM患者具有终生的造血系统恶性肿瘤风险，在具有不同RUNX 1种系突变的家族中，甚至在具有相同RUNX 1突变的单个家族内的受影响个体之间，具有可变的临床表现和疾病转移率。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访问和侵入性程序，如骨髓活检，以监测他们的疾病进展。许多FPD患者不发生白血病的事实表明，RUNX 1突变本身不足以引起白血病;需要额外的体细胞突变，然后进行克隆进化。 为了解决这些问题，以更好地了解FPDMM的临床过程和潜在的致病机制，我们于2019年初在NIH临床中心启动了FPDMM的自然史研究。 https://clinicaltrials.gov/ct2/show/NCT03854318 https://clinicalstudies.info.nih.gov/ProtocolDetails.aspx? A_19-HG-0059.html%20内部RUNX 1 自然史研究的目的是识别和随访FPDMM患者，希望识别可以预测哪些患者将进展和发展为恶性肿瘤的生物标志物，并识别可能影响临床表现、疾病严重程度和恶性肿瘤进展的继发性基因突变。通过我们的研究，我们希望确定RUNX 1突变的基因型-表型相关性，并验证与RUNX 1种系突变合作的第二次命中对白血病发生的重要性。我们希望对患者进行全面的表型分析，以确定生殖系RUNX 1突变的全部表现。 从2021年7月至2022年7月，我们招募了101名参与者参与我们的自然史研究。我们有55名参与者在同一时期访问NIH临床中心（CC）进行年度检查。此外，我们还对无法前往NIH的患者进行了远程医疗，并从当地接受手术的患者那里接收了远程患者样本（血液和骨髓）。对于访问NIH CC的患者，我们进行了临床检查和实验室检查，以记录与FPDMM相关的临床表现，包括造血系统以外的临床表现。我们收集外周血和骨髓样本进行血液学、免疫学和组织学检查和测试。通过在NIH CC收集和远程接收的生物样本，我们一直在进行基因组分析，以确定参与者造血细胞的生殖系和体细胞变化。我们还进行了功能和翻译研究，以确定在我们的患者中检测到的RUNX 1变体的功能后果，使用实验室研究工具以及模型系统，包括来自患者样本的细胞系和动物模型，如斑马鱼和小鼠。 我们的数据将很快提供给研究界，无论是在同行评审期刊上发表的研究文章，还是研究界可以访问的去识别数据库。