The role of clonal hematopoiesis in the development and therapy of myeloid malignancies

项目摘要 不确定潜能的克隆性造血（CHIP）是一种常见的年龄相关性疾病， 与髓系恶性肿瘤相关的克隆体细胞突变在外周血中可检测到， 变异等位基因比例至少为2%。常见的突变基因包括DNMT 3A、TET 2和ASXL 1 基因，所有这些都存在于骨髓恶性肿瘤中，通常在遗传过程的早期获得。 这些癌症的个体发生。CHIP患者没有血液恶性肿瘤或血液改变 计数，但进展为血液恶性肿瘤的风险增加10至50倍，这取决于 克隆的大小和特定的体细胞突变。我们建议研究个体突变的生物学 了解克隆优势的细胞自主和细胞非自主机制。我们将 检查从CHIP到恶性肿瘤的进展以及恶性细胞对躯干的持续依赖性， 突变，从而验证这些突变作为治疗靶点。我们将把这些生物学研究 大规模的遗传研究，以检查恶性转化的风险和临床后果， 特定的突变最后，在实体瘤的背景下，我们将研究CHIP如何产生肿瘤- 功能异常的浸润性巨噬细胞，以及这些体细胞突变的巨噬细胞如何影响 实体瘤生物学、免疫应答和对免疫疗法的应答。

PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-associated condition in which a clonal, somatic mutation that is associated with myeloid malignancies is detectable in the peripheral blood at a variant allele fraction of at least 2%. Commonly mutated genes include the DNMT3A, TET2, and ASXL1 genes, all of which are present in myeloid malignancies and are commonly acquired early in the genetic ontogeny of these cancers. Individuals with CHIP do not have a hematologic malignancy or altered blood counts, but have a 10 to 50-fold increased risk of progression to hematologic malignancy, depending on the size of the clone and the specific somatic mutation. We propose to examine the biology of individual mutations and to understand cell-autonomous and cell non-autonomous mechanisms of clonal dominance. We will examine progression from CHIP to malignancy and the ongoing addiction of the malignant cells to the truncal mutations, thereby validating these mutations as therapeutic targets. We will integrate these biological studies with large-scale genetic studies to examine the risk of malignant transformation and clinical consequences of specific mutations. Finally, in the context of solid tumors, we will examine how CHIP generates tumor- infiltrating macrophages with aberrant function, and how these somatically mutated macrophages influence solid tumor biology, immune response, and response to immunotherapy.