Mechanisms of Erythroid Remission in Diamond Blackfan Anemia (DBA)

摘要 钻石黑粉贫血(DBA)是一种遗传性骨髓衰竭和癌症易感综合征 以大多数患者的严重贫血为特征的，需要长期输注红细胞 或皮质类固醇，这两种治疗方法都有显著和严重的副作用。DBA的遗传原因是 现在被证实在大多数情况下源于负责形成的一系列基因中的一个突变 制造工厂存在于个体的所有细胞--核糖体中。由于核糖体是近几年所需要的 所有的细胞类型，为什么红细胞前体在DBA中优先受到影响的原因还不是很清楚。 重要的是，对DBA患者及其家属的自然病史的研究表明，未知因素可以 修改疾病的严重程度。携带DBA突变的家庭中的一些人可能患有经典型的， 输血依赖型贫血，而其他拥有相同基因突变的人可能受到的影响很小， 没有贫血，如果有血液学症状的话也很轻微。在另一种情况下，DBA患者 以前需要对DBA进行大量的医疗治疗，例如依赖红细胞输注，可能 停止需要治疗，并在无限期内自行维持足够的红细胞水平 时间到了。这种情况被称为“血液系统缓解”，每五到十个人中就会有一个人发生这种情况。 需要治疗的DBA患者。它也是可逆的，这意味着处于血液系统缓解状态的患者 在某种程度上，可能会失去缓解，并在以后变得依赖于药物治疗，再次在不可预测的 时尚。与其他特征一起，DBA的血液学缓解的可逆性表明它可能 由发育中的红血球或其祖细胞的表观遗传因素所介导。 融合了包括细胞培养技术在内的新方法，允许扩增患者来源的 人类血祖细胞转化为红细胞，这是一项技术创新，使全基因组测量 从有限的细胞数量中提取表观经济学因素，以及基于系统的数据分析计算方法 详细分析DBA血液学缓解的分子机制是可行的。在……里面 这项创新的工作，我们专注于一个单一的目标，以开发新的途径来理解血液学 DBA的表型：缓解的表观遗传机制的定义。利用基因组规模的DNA研究 中国人红细胞前体的甲基化、染色质占有率和特性以及RNA转录 在血液病缓解期患者中，我们将确定绕过红细胞的调节通路的变化 DBA中的缺陷。因此，这项研究的发现将确定开发医疗疗法的新方向 改善DBA的贫血。更广泛地说，这项工作对于理解组织特异性是多么重要。 在人类核糖体疾病中受到调节。

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.