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

年龄相关克隆性造血(ARCH或简称CH)被定义为携带特定的、破坏性的和反复发生的遗传变异的造血干细胞和祖细胞(HSPC)在未明确诊断为血液系统恶性肿瘤的个体中的逐渐克隆性扩张。越来越清楚的是，CH与许多病理状态有关，并增加了患血癌的风险。影响CH增龄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，骨髓从红色向富含脂肪细胞的黄色骨髓转变。以前的研究表明，正常的HSCs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)积累可能为携带白血病前突变(PLM)的特定白血病前干细胞和祖细胞(PreL-HSPC)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，以研究人类和小鼠的PreL-HSPC在FBM中的行为。将来自AML患者(DNMT3a，NPM1突变)的原代人preL-HSPC移植到FBM中，与没有FBM的对照小鼠相比，植入率提高。我们进一步证明了R882H+/-小鼠来源的骨髓HSPC，移植到患有FBM的NSG小鼠中的比例显著高于对照组。此外，将R882H+/-来源于老龄小鼠(一岁)的BM注射到FBM小鼠体内，植入率增加了10倍。值得注意的是，在患有FBM的NSG小鼠中，没有检测到Srsf2P95HxVAV来源的BM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。剩下的悬而未决的问题是--与WT HSPC相比，FBM专门为携带DNMT3A的PreL-HSPC提供优势的潜在分子机制是什么？FBM与携带其他突变(如ASXL1、剪接体突变)的preL-HSPC之间的相互作用是什么？骨髓中稳定的白血病前期细胞的位置是什么？FBM对幼年和老年小鼠的正常造血有什么影响？这项研究将是两个专业知识高度互补的实验室之间的合作努力。盖革实验室在啮齿动物造血干细胞的老化和骨髓微环境的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拥有专业知识。研究BM微环境和人类HSCs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.