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）和骨髓增生异常综合征（MDS）。 阵发性睡眠性血红蛋白尿症（PNH）是一种以造血功能衰竭、干细胞减少、 细胞衰竭和以体细胞基因组损伤的存在为标志的不同程度的克隆性。这些 条件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 提供了突破性的发现，对理解生理病理生理学 在造血机制和超越整个血液学领域。我早期的主要焦点是 作为医生科学家和血液学家的科学生涯一直在研究免疫发病机制， 干细胞计数、干细胞损伤机制和BMFS的分子遗传学。后面的主题 最初包括发现新的体细胞和生殖系病变，随后过渡到机制性病变。 问题研究这些调查线，特别是在这个R35相关，产生了重要的线索， 突变谱，后来导致越来越多的赞赏的作用，克隆层次， 动力学不仅在MDS中，而且在AA和PNH中。我们的团队为此做出了重大贡献。 通过NHLBI和其他来源的持续供资，取得了进展。我们的经验，承诺 到外地，并建立基础设施提供了一个坚实的基础，拟议扩大正在进行的分子 研究转向新的范式转变的科学目标。通过利用最新的分子 体细胞和生殖系突变的发现，并通过阐明其机制的进展， 因此，我们认为，现在是推进转化目标的时候了， 医疗护理，包括BMFS的诊断和治疗。此类调查还将有助于 提高对由选定的常见和重要的疾病亚组介导的基本疾病机制的理解 体细胞突变我们将使用最新的技术，包括单细胞分选和测序， 研究克隆结构，以确定可靶向的早期事件，并确定克隆结构的依赖性。 细胞对这些事件后，收购亚克隆病变。这些基因组研究还将涉及 生殖系病变及其在成人骨髓基质细胞晚期表现中的作用。它们将为 旨在开发概念上新的治疗策略的机制研究。这一主题将首先 涉及TET2和其它双加氧酶、DNMT3A和其它组蛋白和DNA甲基化酶以及剪接体 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 通过会聚途径的存在来确定疾病亚组，结果将为 合理选择最合适的靶点，以开发新的治疗策略。

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.