Delineating Drivers of Inflammation and Progression in Clonal Hematopoiesis

(请保存在Word中，不要保存为PDF) 在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 在没有血液系统恶性肿瘤的情况下，造血干细胞和祖细胞(HSPC)在衰老过程中通常会发生与白血病相关的体细胞突变。携带这些突变的细胞对骨髓微环境施加压力，扰乱正常的造血，无论是干细胞的内在变化还是微环境的扰动，都会导致克隆性扩张、骨髓衰竭和恶性风险。然而，只有一小部分接受芯片的患者进展到显著的骨髓破坏，以及了解哪些人将进展仍然是该领域的一个显著差距。使用系统的血液学方法，我们提出了一个研究过程，以确定在人类芯片中导致克隆扩张和疾病进展的因素。我们的长期目标是剖析克隆性髓系疾病的发病机制，并确定逆转疾病进展的治疗靶点。众所周知，炎症与mTET2芯片有关，但在人类中的免疫效应和表观遗传水平的原因尚未阐明。这笔过渡性资金将使我们能够优化将基因型输入到转录单细胞数据的方法。这将扩大我们对TET2缺失的表观遗传反应的表征，并识别导致免疫微环境紊乱的机械性变化。最终，这将直接加强我们下一次将这项工作作为扩大的研究项目拨款提交。

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Somatic, leukemia-associated mutations commonly occur in hematopoietic stem and progenitor cells (HSPC) during aging in the absence of hematologic malignancy. Cells harboring these mutations exert stress on the bone marrow microenvironment, disrupting normal hematopoiesis, both with respect to stem cell intrinsic changes and microenvironmental perturbations, leading to clonal expansion, bone marrow failure, and risk of malignancy. However, only a fraction of individuals with CHIP progress to significant bone marrow disruption and understanding which individuals will progress remains a significant gap in the field. Using a systems hematology approach, we propose a course of study to identify factors that contribute to clonal expansion and disease progression in human CHIP. Our long-term goal is to dissect the pathogenic mechanisms of clonal myeloid disorders and identify therapeutic targets to reverse disease progression. Inflammation has a well-known association with mTET2 CHIP, but the immune effects in humans and causes at the epigenetic levels have not been elucidated. This bridge funding will allow us to optimize our approach to imputing genotype onto transcriptional single cell data. It will expand our effort to characterize the epigenetic responses to TET2 loss and identify mechanistic changes that precipitate a disrupted immune microenvironment. Ultimately, this will directly strengthen our next submission of this work as an expanded research project grant.