Dynamics of somatic mosaicism in the murine hematopoietic system

小鼠造血系统体细胞嵌合的动力学

• 批准号: 497777320
• 负责人: Dr. Alexander Gerbaulet
• 金额: --
• 依托单位: Deutsches Krebsforschungszentrum (DKFZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497777320?language=en
• 关键词: Dynamics; somatic; mosaicism; murine; hematopoietic

Cell clones harboring somatic mutations known as cancer drivers have now been found in many phenotypically normal tissues and accumulate with aging. Hematopoiesis has emerged as a paradigm of such somatic mosaicism; large hematopoietic stem cell (HSC) clones with leukemic driver mutations are frequently found in healthy elderly. These observations raise the question which cellular mechanisms counteract leukemogenesis, and whether there are early warning signs that these protective mechanisms are breaking down. A clue is provided by the recent observation, by us and others, that HSC in mice show a remarkable pattern of activity: While being quiescent for several months, HSCs rarely but reliably become active to spawn a multipotent progenitor (MPP). MPPs exhibit extensive self-renewal in vivo and maintain production of blood cells long-term even when HSCs are depleted. Hence, we hypothesize that the rare HSC output functions to prevent excessive accumulation of mutations in more rapidly dividing progenitors. To test this, we will make use of mouse models that: (i) allow the selective depletion of HSCs, (ii) genetically perturb epigenetic regulation by Tet2 loss-of-function, decreasing HSC output and increasing self-renewal, and (iii) globally increase mutation rate across the genome. We will quantify the accumulation of somatic mutations in single HSCs and progenitors as well as in bulk cells, yielding complementary information on mutation count in single cells and on the frequency distribution of somatic variants in sorted populations, respectively. Using mathematical approaches from population genetics, we will infer from these comprehensive data the clonal evolution of hematopoiesis during normal aging and in response to the perturbations. Moreover, we will reconstruct evolutionary paths to malignancy triggered by Tet2 loss-of-function and increased mutation rate. This project will yield unprecedented insight into somatic mosaicism in mice and origins of leukemogenesis. Given that myelodysplastic disorders in humans frequently give rise to acute leukemia, we expect that our findings will inform novel approaches at understanding, and early diagnosing, this transition to leukemia.

现在，在许多表型正常的组织中发现了含有体细胞突变的细胞克隆，这些体细胞突变被称为癌症驱动因子，并随着年龄的增长而积累。造血已经成为这种体细胞嵌合体的范例；具有白血病驱动突变的大型造血干细胞（HSC）克隆常见于健康老年人。这些观察结果提出了一个问题，即哪些细胞机制可以对抗白血病的发生，以及是否存在这些保护机制正在崩溃的早期预警信号。我们和其他人最近的观察提供了一个线索，小鼠中的HSC显示出一种显著的活动模式：在几个月的静止状态下，HSC很少但可靠地变得活跃以产生多能祖细胞（MPP）。mpp在体内表现出广泛的自我更新，即使造血干细胞耗尽，也能长期维持血细胞的产生。因此，我们假设罕见的HSC输出功能可以防止更快分裂的祖细胞中突变的过度积累。为了验证这一点，我们将利用小鼠模型：(i)允许HSC的选择性消耗，（ii）通过Tet2功能丧失对表观遗传调控的遗传干扰，减少HSC输出并增加自我更新，以及（iii）在整个基因组中增加突变率。我们将量化单个造血干细胞和祖细胞以及散装细胞中体细胞突变的积累，分别获得单细胞突变计数和分类群体中体细胞变异频率分布的补充信息。利用群体遗传学的数学方法，我们将从这些综合数据中推断出正常衰老过程中造血的克隆进化和对扰动的响应。此外，我们将重建由Tet2功能丧失和突变率增加引发的恶性肿瘤的进化路径。这个项目将对小鼠体内的体细胞嵌合体和白血病发生的起源产生前所未有的见解。鉴于人类骨髓增生异常疾病经常引起急性白血病，我们期望我们的研究结果将为理解和早期诊断这种向白血病的转变提供新的方法。