Mechanisms of Erythroid Remission in Diamond Blackfan Anemia (DBA)

钻石黑扇贫血 (DBA) 红系缓解机制

• 批准号: 10350576
• 负责人: Jason Eli Farrar
• 金额: $ 30.6万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350576
• 关键词: Adrenal Cortex Hormones; Affect; Anemia; Apoptotic; Biochemical; Biological Models; Blood; Bone Marrow; Bone Marrow Transplantation; Bone marrow failure; Bypass; Cell Count; Cell Culture Techniques; Cells; Cessation of life; ChIP-seq; Characteristics; Chromatin; Clinical; Computing Methodologies; DNA Methylation; Data; Data Analyses; Defect; Dependence; Diamond; Diamond-Blackfan anemia; Disease; Disease remission; Enhancers; Epigenetic Process; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythroid Cells; Failure; Family; Family member; Funding Opportunities; GATA1 gene; Gene Family; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genomics; Globin; Goals; Hematology; Hematopoiesis; Heme; Hemoglobin; Human; Hypermethylation; Impairment; Individual; Inherited; Lead; Life; Maintenance; Malignant Neoplasms; Manufactured form; Measurement; Mediating; Medical; Methods; Methylation; Modeling; Molecular Analysis; Mutation; Natural History; Nature; Non-Malignant; Pathogenicity; Pathway interactions; Patients; Phenotype; Plants; Play; Predisposition; Process; Production; Prognostic Marker; Proteins; RNA; Regulator Genes; Regulatory Pathway; Research Project Grants; Ribosomal Proteins; Ribosomes; Role; Sampling; Severity of illness; Short Interspersed Nucleotide Elements; Site; Specificity; Specimen; Syndrome; System; Systems Biology; TP53 gene; Technology; Therapeutic Intervention; Time; Tissues; Transfusion; Translations; Variant; Work; adenosine deaminase; base; bone marrow failure syndrome; cancer predisposition; causal variant; cell type; clinical remission; congenital anomaly; data registry; epidemiologic data; epigenomics; erythroid differentiation; experience; genetic pedigree; genome-wide; genome-wide analysis; human disease; improved; innovation; interest; new therapeutic target; novel; progenitor; promoter; side effect; stem; stem cells; transcription factor

Abstract Diamond Blackfan anemia (DBA) is an inherited bone marrow failure and cancer predisposition syndrome characterized in most patients by severe anemia that requires long term treatment with red blood cell transfusions or corticosteroids, both treatments carrying significant and serious side-effects. The genetic cause for DBA is now established to stem in most cases from mutations in one among a family of genes responsible for forming the manufacturing plant present in all of an individual’s cells, the ribosome. Since ribosomes are needed in nearly all cell types, the reason that red cell precursors are preferentially affected in DBA is not well understood. Importantly, study of the natural history of patients and families with DBA reveals that unknown factors can modify the severity of the disease. Some individuals in a family carrying a DBA mutation may have classic, transfusion-dependent anemia while others, who share the same gene mutation, may be minimally affected, without anemia and subtle if any hematologic manifestations. In another circumstance, DBA patients who previously required significant medical treatment for DBA, such as dependence on red cell transfusions, may stop requiring medical treatment and maintain adequate red cell levels on their own for an indefinite period of time. This condition is termed ‘hematologic remission’ and unpredictably occurs in one out of every five to ten DBA patients who require treatment. It is also reversible, meaning that a patient who is in hematologic remission at one point may lose that remission and become dependent on medical therapy later, again in an unpredictable fashion. Along with other features, the reversible nature of hematologic remission in DBA suggests that it may be mediated by epigenetic factors in developing red cells or their progenitors. A confluence of novel methods including cell culture techniques that allow expansion of patient-derived human blood progenitor cells into red cells, technical innovations that allow genome-wide measurement of epigenomic factors from limited cell numbers, and systems-based computational methods for data analysis make detailed analysis of the molecular mechanisms underlying hematologic remission in DBA feasible for pursuit. In this innovative work, we focus on a single aim to develop new pathways for understanding the hematologic phenotype in DBA: definition of the epigenetic mechanisms of remission. Using genome-scale studies of DNA methylation, chromatin occupancy and characterization, and RNA transcription in red cell precursors from patients in hematologic remission, we will identify the changes in regulatory pathways that bypass the red cell defect in DBA. Findings from this study will thus identify new directions for developing medical therapies to ameliorate anemia in DBA. More broadly, this work will be important in understanding how tissue specificity is modulated in the human ribosomopathies.

摘要 DiamondBlackfan贫血（DBA）是一种遗传性骨髓衰竭和癌症易感综合征 大多数患者的特征是严重贫血，需要长期输注红细胞治疗 或皮质类固醇，这两种治疗都具有显著和严重的副作用。DBA的遗传原因是 现在已经确定，在大多数情况下，起源于一个负责形成 存在于个体所有细胞中的制造工厂，核糖体。由于核糖体几乎是 所有的细胞类型，红细胞前体细胞在DBA中优先受影响的原因还不清楚。 重要的是，对DBA患者和家庭自然史的研究表明，未知因素可能导致DBA的发生。 改变疾病的严重程度。携带DBA突变的家族中的一些个体可能具有经典的， 输血依赖性贫血，而其他人，谁共享相同的基因突变，可能会受到最小的影响， 没有贫血和轻微的血液学表现。在另一种情况下，DBA患者 以前需要对DBA进行重要的药物治疗，例如依赖红细胞输注， 停止需要药物治疗，并在无限期内自行维持足够的红细胞水平， 时间这种情况被称为'血液缓解'和不可预测的发生在一个每五至十个 需要治疗的DBA患者。它也是可逆的，这意味着血液学缓解的患者 在某一点上可能会失去缓解，并成为依赖于药物治疗后，再次在一个不可预测的 时尚.沿着其他特征，DBA血液学缓解的可逆性表明， 由发育中的红细胞或其祖细胞中的表观遗传因子介导。 包括细胞培养技术在内的新方法的汇合，允许扩增患者来源的细胞， 人类血液祖细胞转化为红细胞，技术创新，允许全基因组测量 表观基因组因素从有限的细胞数量，和系统为基础的计算方法的数据分析， 详细分析DBA血液学缓解的分子机制。在 这项创新的工作，我们专注于一个单一的目标，开发新的途径，了解血液学 DBA的表型：缓解的表观遗传机制的定义。利用DNA的基因组规模研究 甲基化，染色质占有率和表征，以及来自红细胞前体的RNA转录。 对于血液学缓解的患者，我们将确定绕过红细胞的调节途径的变化， DBA的缺点因此，这项研究的结果将为开发医学疗法确定新的方向， 改善DBA贫血。更广泛地说，这项工作将是重要的，在了解组织特异性是如何 在人类核糖体病中被调节。

项目成果

L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry.

• DOI: 10.1002/pbc.28748
• 发表时间: 2020-12
• 期刊: Pediatric blood & cancer
• 影响因子: 3.2
• 作者: Vlachos A;Atsidaftos E;Lababidi ML;Muir E;Rogers ZR;Alhushki W;Bernstein J;Glader B;Gruner B;Hartung H;Knoll C;Loew T;Nalepa G;Narla A;Panigrahi AR;Sieff CA;Walkovich K;Farrar JE;Lipton JM
• 通讯作者: Lipton JM