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

年龄相关性克隆造血（ARCH或简称CH）被定义为在没有明确血液恶性肿瘤诊断的个体中，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（HSPCs）逐渐克隆扩增。越来越清楚的是，CH与许多病理状态和血癌风险增加有关。影响CH随年龄增长的环境因素之一是脂肪性骨髓（FBM）。出生时，骨髓（BM）含有功能活跃的造血组织，称为红骨髓。随着年龄的增长，骨髓从红骨髓向富含脂肪细胞的黄色骨髓转移。以往的研究表明，正常造血干细胞受到脂肪性脑基质微环境的影响。在这里，我们假设年龄相关的骨髓脂肪（BMF）积累可能对携带白血病前突变（pLM）的特异性白血病前干细胞和祖细胞（pre -l - hspcs）提供选择性优势。为了支持这一假设，Shlush和Geiger实验室在NSG小鼠中建立并验证了FBM模型，以研究人类和小鼠前l - hspcs在FBM中的行为。将来自AML患者（DNMT3a， NPM1突变）的原代人前l - hspcs移植到FBM中，与没有FBM的对照小鼠相比，其植入增强。我们进一步证明，与对照组相比，R882H+/-小鼠衍生的BM HSPCs在FBM的NSG小鼠中移植的数量显著增加。此外，当注射到FBM小鼠体内时，检测到老年小鼠（1岁）R882H+/-来源的BM的植入量增加了10倍。值得注意的是，NSG小鼠FBM中未检测到Srsf2P95HxVAV源性BM的植入增加。这些结果首次证明FBM对携带R882H的白血病前期细胞具有选择性优势。仍未解决的问题是：与WT型HSPCs相比，FBM对携带DNMT3A的pre - l -HSPCs的优势是什么潜在的分子机制？FBM与携带其他突变（如ASXL1、剪接体突变）的前l - hspcs的相互作用是什么？BM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功能有什么影响？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。盖格实验室在啮齿动物造血干细胞老化和骨髓微环境变化方面获得了专业知识。Shlush实验室在人类HSC老化、克隆造血和异种移植方面具有专长。研究骨髓微环境与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的结合。

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.