Age-related clonal hematopoiesis and its link to age-related changes in the bone marrow microenvironment

年龄相关的克隆造血及其与骨髓微环境年龄相关变化的联系

• 批准号: 495274811
• 负责人: Professor Dr. Hartmut Geiger
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 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/495274811?language=en
• 关键词: Age; related; clonal; hematopoiesis; its

Age-related clonal hematopoiesis (ARCH or simply CH) is defined as the gradual, clonal expansion of hematopoietic stem and progenitor cells (HSPCs) carrying specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematological malignancies. It is becoming clearer that CH is associated with many pathological states and increased risk for blood cancers. One of the environmental factors that may influence CH with age is fatty bone marrow (FBM). At birth the bone marrow (BM) contains functionally active hematopoietic tissue, known as red BM. During aging there is a shift from red marrow to adipocyte-enriched yellow BM. Previous studies suggested that normal HSCs are influenced by the fatty BM microenvironment. Here, we hypothesize that age related bone marrow fat (BMF) accumulation might provide selective advantage to specific pre-leukemic stem and progenitor cells (preL-HSPCs) carrying pre-leukemic mutations (pLM). To support this hypothesis, the Shlush and Geiger laboratories established and validated a FBM model in NSG mice to study both human and murine preL-HSPCs behavior within FBM. Transplantation of primary human preL-HSPCs from an AML patient (DNMT3a, NPM1 mutations) into FBM resulted in enhanced engraftment compared to control mice without FBM. We further demonstrate that R882H+/- mice derived BM HSPCs, engrafted significantly higher in NSG mice with FBM compared to controls. Moreover, ten-fold increase in engraftment of R882H+/- derived BM from aged mice (one year old) was detected when injected into a FBM mice. Notably, no increase in engraftment of Srsf2P95HxVAV derived BM was detected in NSG mice with FBM. These results demonstrate for the first time that the FBM provides a selective advantage to pre-leukemic cells carrying R882H. Remaining unanswered questions are - what are the underlying molecular mechanisms conferring the advantage provided by the FBM specifically to preL-HSPCs carrying DNMT3A in comparison to WT HSPCs? What is the interplay of FBM with preL-HSPCs carrying other mutations, like ASXL1, spliceosome mutations? What is the location of the settled preleukemic cells in BM? What are the effects of FBM on normal hematopoiesis in young and aged mice? This study will be a collaborative effort between two laboratories with a highly complementary expertise. The Geiger lab gained expertise in the aging of rodents HSCs and in changes in the BM microenvironment. The Shlush lab has expertise in human HSC aging, clonal hematopoiesis and xenografts. Studying the interaction between the BM microenvironment and human HSCs demands the combination of expertise of both laboratories.

造血相关克隆性造血（CD 4或简称CH）是指在未明确诊断为血液恶性肿瘤的个体中，携带特异性、破坏性和复发性遗传变异的造血干细胞和祖细胞（HSPC）的逐渐克隆扩增。越来越清楚的是，CH与许多病理状态和血液癌症风险增加有关。随着年龄的增长，可能影响CH的环境因素之一是脂肪骨髓（FBM）。出生时，骨髓（BM）含有功能活跃的造血组织，称为红色BM。在衰老过程中，骨髓从红色转变为富含脂肪细胞的黄色BM。以前的研究表明，正常的HSC受到脂肪BM微环境的影响。在这里，我们假设年龄相关的骨髓脂肪（BMF）积累可能提供选择性优势，特定的白血病前干细胞和祖细胞（前L-HSPC）携带白血病前突变（pLM）。为了支持这一假设，Shlush和盖革实验室在NSG小鼠中建立并验证了FBM模型，以研究人和鼠preL-HSPC在FBM中的行为。与没有FBM的对照小鼠相比，将来自AML患者（DNMT 3a，NPM 1突变）的原代人preL-HSPC移植到FBM中导致植入增强。我们进一步证明，与对照相比，R882 H +/-小鼠衍生的BM HSPC在具有FBM的NSG小鼠中移植显著更高。此外，当注射到FBM小鼠中时，检测到来自老年小鼠（1岁）的R882 H +/-衍生的BM的植入增加10倍。 值得注意的是，在患有FBM的NSG小鼠中没有检测到Srsf 2 P95 HxVAV衍生的BM的植入增加。这些结果首次证明了FBM对携带R882 H的前白血病细胞提供了选择性优势。剩余的未回答的问题是-与WT HSPC相比，赋予FBM特异性地提供给携带DNMT 3A的preL-HSPC的优势的潜在分子机制是什么？FBM与携带其他突变（如ASXL 1、剪接体突变）的preL-HSPC之间的相互作用是什么？在骨髓中沉淀的白血病前期细胞的位置是什么？FBM对年轻和老年小鼠的正常造血有什么影响？ 这项研究将是两个具有高度互补专业知识的实验室之间的合作努力。盖革实验室获得了啮齿动物HSC老化和BM微环境变化方面的专业知识。Shlush实验室在人类HSC老化，克隆造血和异种移植方面具有专业知识。研究骨髓微环境和人类造血干细胞之间的相互作用需要两个实验室的专业知识相结合。