Pre-Leukemic Hematopoietic Stem Cells and Clonal Evolution in Human AML

人类 AML 中白血病前期造血干细胞和克隆进化

• 批准号: 9113347
• 负责人: Ravindra Majeti
• 金额: $ 32.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-03 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113347
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Allogenic; Architecture; Automobile Driving; Biological Assay; Blood Cells; Bone Marrow; CD19 gene; Cell division; Cell physiology; Cells; Clinical; Clonal Evolution; Complex; DNA Sequence; Development; Diagnosis; Diagnostic; Disease; Elderly; Engineering; Exhibits; Gene Frequency; Genes; Genome; Genomics; Genotype; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; High Dose Chemotherapy; Homologous Transplantation; Human; In Vitro; Individual; Investigation; Leukemic Cell; Leukemic Hematopoietic Stem Cell; Life; Longevity; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Measures; Modeling; Multipotent Stem Cells; Mutate; Mutation; Myelogenous; Myeloid Cells; Outcome; Pathogenesis; Patients; Pattern; Phenotype; Population; Production; Property; Recording of previous events; Recurrence; Recurrent disease; Refractory; Relapse; Reporting; Residual state; Resistance; Stem cells; Survival Rate; System; Time; United States; Xenograft procedure; base; chemotherapeutic agent; chemotherapy; clinical remission; hematopoietic cell transplantation; improved; in vivo; leukemia; leukemogenesis; new therapeutic target; next generation; novel; progenitor; self-renewal; standard of care; success; targeted treatment; treatment response

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by the accumulation of immature myeloid cells defective in their maturation and function. AML affects 13,000 adults annually in the United States, most of them over the age of 65. Even with standard aggressive treatments with chemotherapy and/or allogeneic transplantation, five-year overall survival is between 30-40%, and much lower for those over age 65. This poor overall survival rate is primarily due to chemotherapy-resistant and/or relapsed disease that is often refractory to additional therapies. Over the last 5 years, next generation DNA sequencing has been applied to characterizing human AML genomes with great success in identifying most recurrently mutated genes. Importantly, these genomic studies have demonstrated that most cases of AML are associated with mutations in multiple genes, often occurring with different allelic frequencies, suggesting a complex clonal architecture and developmental history. These findings raise many important questions, one of which is how multiple mutations accumulate in a single clonal lineage of hematopoietic cells. Normal hematopoiesis is organized as a cellular hierarchy initiated and maintained by hematopoietic stem cells (HSC) that give rise to intermediate progenitors and eventually all the differentiated cells of the blood. In myeloid differentiation, HSC are the only long-lived self-renewing population, as all other cells and progenitors have a limited lifespan typically measured in days or weeks. From these considerations, a model has been proposed that leukemogenic mutations must serially accumulate in HSC. Therefore, HSC containing some, but not all, leukemogeneic mutations, termed pre-leukemic HSC, must persist at diagnosis and may contribute to relapsed disease. Recently, evidence supporting this model of clonal evolution of pre-leukemic HSC in human AML was reported for a small set of primary patient cases. This proposal aims to further investigate pre-leukemic HSC in human AML based on the hypothesis that leukemogenic mutations accumulate in clones of HSC and that these pre-leukemic HSC clones are critical for disease pathogenesis and relapse. The first aim is to determine the clonal evolution of pre-leukemic HSC in AML from a diversity of molecularly-defined diagnostic AML cases, and determine if there are common patterns of clonal evolution using a combination of next generation DNA sequencing, single cell genotyping, and functional xenotransplantation assays. The second aim is to determine the effect of pre-leukemic mutations on HSC self-renewal, proliferation, differentiation, and chemosensitivity using both in vitro and in vivo assays. The third aim is to identify and track pre-leukemic HSC during the course of treatment and response in individual AML patients including both clinical remission and clinical relapse, with the goal of determining if such cells contribute to relapsed disease. Ultimately, investigation of pre-leukemic HSC and the corresponding founding mutations will advance our understanding of leukemogenesis, and will be critical to the development of novel curative targeted AML therapies.

描述（由申请人提供）：急性髓系白血病（AML）是一种侵袭性骨髓恶性肿瘤，其特征是成熟和功能有缺陷的未成熟髓系细胞的积累。在美国，AML 每年影响 13,000 名成年人，其中大多数年龄超过 65 岁。即使采用化疗和/或同种异体移植等标准积极治疗，五年总生存率也在 30-40% 之间，对于 65 岁以上的患者来说，五年总生存率要低得多。 65 岁。总生存率低下主要是由于化疗耐药和/或疾病复发，而这些疾病通常难以通过其他疗法治愈。在过去 5 年里，下一代 DNA 测序已被应用于表征人类 AML 基因组，并在识别大多数经常突变的基因方面取得了巨大成功。重要的是，这些基因组研究表明，大多数 AML 病例与多个基因突变有关，通常以不同的等位基因频率发生，表明其具有复杂的克隆结构和发育历史。这些发现提出了许多重要问题，其中之一是多个突变如何在造血细胞的单个克隆谱系中积累。正常造血是由造血干细胞 (HSC) 启动和维持的细胞层次结构组成，造血干细胞产生中间祖细胞，并最终产生血液的所有分化细胞​​。在骨髓分化中，HSC 是唯一长寿的自我更新群体，因为所有其他细胞和祖细胞的寿命有限，通常以天或周为单位。从这些考虑出发，提出了一个模型，即白血病突变必须在 HSC 中连续积累。因此，含有一些（但不是全部）白血病突变的 HSC（称为白血病前 HSC）必须在诊断时持续存在，并可能导致疾病复发。最近，在一小部分原发性患者病例中报道了支持人类 AML 中白血病前 HSC 克隆进化模型的证据。该提案旨在进一步研究人类 AML 中的白血病前 HSC，其假设是致白血病突变在 HSC 克隆中积累，并且这些白血病前 HSC 克隆对于疾病发病机制和复发至关重要。第一个目标是从多种分子定义的诊断性 AML 病例中确定 AML 中白血病前 HSC 的克隆进化，并结合下一代 DNA 测序、单细胞基因分型、和功能性异种移植测定。第二个目的是利用体外和体内试验确定白血病前期突变对 HSC 自我更新、增殖、分化和化疗敏感性的影响。第三个目标是在个体 AML 患者的治疗和反应过程中识别和跟踪白血病前 HSC，包括临床缓解和临床复发，目的是确定这些细胞是否导致疾病复发。最终，对白血病前 HSC 和相应的基础突变的研究将增进我们对白血病发生的理解，并且对于开发新型治疗性靶向 AML 疗法至关重要。