Therapeutic Implications of Molecular Defects in Bone Marrow Failure

摘要 骨髓衰竭综合征(BMFS)包括骨髓增生异常综合征(MDS)、再生障碍性贫血(AA)和 阵发性睡眠性血尿(PNH)是一种以失血为特征的疾病 细胞衰竭和不同程度的克隆性，以体细胞基因组损伤为特征。这些 疾病不仅具有日益增长的社会经济和医学重要性，而且其基础研究也 为理解生理学和病理生理学提供了开创性的发现 整个血液学领域的造血内和外的机制。我早期的主要关注点是 作为内科科学家和血液学家的科学生涯一直在研究免疫发病机制，方法 干细胞计数、干细胞损伤机制及骨髓间充质干细胞分子遗传学。后一主题 最初包括发现新的体细胞和生殖细胞损伤，随后过渡到机械论 学习。这些调查路线，特别是与R35相关的，产生了关于 MDS中的突变谱以及后来导致对克隆层次和 不仅在MDS，而且在AA和PNH中也有动态变化。我们的团队为这些做出了重大贡献 来自NHLBI和其他来源的持续资金使预付款成为可能。我们的经验、承诺 和创建的基础设施为正在进行的分子的拟议扩展提供了坚实的基础 朝向新的范式转变的科学目标的研究。通过利用最新的分子 体细胞和生殖系突变的发现以及阐明其机制的进展 考虑到影响，我们认为现在是时候推进翻译目标，以便在以下方面取得切实进展 BMFS的医疗护理，包括诊断和治疗。这类调查还将有助于 通过选定常见和重要的子集提高对基本疾病机制的理解 体细胞突变。我们将使用最新的技术，包括单细胞分类和测序，以进一步 研究克隆结构以识别目标早期事件，并确定克隆的依赖性 在获得亚克隆性病变后，这些事件上的细胞。这些基因组研究还将涉及 成人骨髓间质纤维化的胚系损害及其对晚期表现的贡献。他们将提供基材用于 旨在开发概念上的新治疗策略的机械学研究。这一主题最初将 涉及TET2和其他双加氧酶、DNMT3A等组蛋白和DNA甲基酶和剪接体 突变。这些研究还将确定生殖系改变的影响，并使用综合方法 通过聚合路径的存在来识别疾病亚组，结果将为 合理选择最合适的靶点，开发新的治疗策略。

ABSTRACT Bone marrow failure syndromes (BMFS) include myelodysplastic syndrome (MDS), aplastic anemia (AA) and paroxysmal nocturnal hemoglobiuria (PNH) and are diseases characterized by failed blood production, stem cell failure and various degrees of clonality marked by the presence of somatic genomic lesions. These conditions have not only a growing socioeconomic and medical importance, but also their basic study has provided ground-breaking discoveries with implications for the understanding the physiologic pathophysiologic mechanisms within hematopoiesis and beyond for the whole field of hematology. The main focus of my early scientific career as physician scientist and hematologist has been on study immune pathogenesis, ways of stem cell enumeration, mechanisms of stem cell damage and molecular genetics of BMFS. The latter themes initially included discovery of new somatic and germ line lesions and subsequently transitioned to mechanistic studies. These lines of investigations, specifically pertinent in this R35, yielded important clues as to the mutational spectrum in MDS and later led to the growing appreciation of the role of clonal hierarchy and dynamics not only in MDS, but also in AA and PNH. Our team has made significant contribution to these advances made possible by a continuous funding from NHLBI and other sources. Our experience, commitment to the field, and created infrastructure provide a solid base for proposed expansions of ongoing molecular studies towards new paradigm-shifting scientific goals. By taking advantage of the newest molecular discoveries of somatic and germ line mutations and through progress in clarifying their mechanistic consequences, we believe that it is now time to advance translational goals to make tangible advances in medical care including diagnostics and therapeutics for BMFS. Such investigations would also contribute to improved understanding of basic disease mechanisms mediated by selected subset of common and important somatic mutations. We will use the newest technologies, including single cell sorting and sequencing, to further study the clonal architecture to identify targetable early events and also determine the dependence of clonal cells on these events following acquisition of subclonal lesions. These genomic investigations will involve also germ line lesions and their contribution of late manifestation of adult BMFs. They will provide substrates for mechanistic studies aiming at development of conceptually new therapeutic strategies. This theme will initially involve TET2 and other dioxygenases, DNMT3A and other histone and DNA methylases and spliceosomal mutations. These studies will also define the impact of germ line alteration and using integrative approaches identify disease subgroups by the presence of convergent pathways and results will provide a canvas for the rational selection of most suitable targets for development of new treatment strategies.