Leukemias arise from recurrent clonal mutations in hematopoietic stem/progenitor cells (HSPCs) that cause profound changes in the bone marrow microenvironment (BMM) favoring leukemic stem cell (LSC) growth over normal HSPCs. Understanding the cross talk between preleukemic mutated HSPCs and the BMM is critical to develop novel therapeutic strategies to prevent leukemogenesis. We hypothesize that preleukemic-LSCs (pLSCs) induce BMM changes critical for leukemogenesis. Using our AML-murine model, we performed single-cell RNA-sequencing of preleukemic BMM (pBMM) cells. We found normal HSC (nHSC)-regulating LepR+ mesenchymal stem cells, and endothelial cells were decreased, along with increases in CD55+ fibroblasts and pericytes. Preleukemic CD55+ fibroblasts had higher proliferation rates and decreased collagen expression, suggesting extracellular matrix remodeling during leukemogenesis. Importantly, co-culture assays found preleukemic CD55+ fibroblasts expanded pLSCs significantly over nHSCs. In conclusion, we have identified a distinct pBMM and a novel CD55+ fibroblast population that is expanded in pBMM that promote fitness of pLSCs over nHSCs.

白血病是由造血干细胞/祖细胞 （HSPC） 的复发性克隆突变引起的，这些突变会导致骨髓微环境 （BMM） 发生深刻变化，有利于白血病干细胞 （LSC） 的生长而不是正常的 HSPC。了解白血病前期突变 HSPC 和 BMM 之间的串扰对于开发防止白血病发生的新型治疗策略至关重要。我们假设白血病前期 LSC （pLSC） 诱导对白血病发生至关重要的 BMM 变化。使用我们的 AML-小鼠模型，我们对白血病前体 BMM （pBMM） 细胞进行了单细胞 RNA 测序。我们发现正常的 HSC （nHSC） 调节 LepR+ 间充质干细胞，内皮细胞减少，CD55+ 成纤维细胞和周细胞增加。白血病前期 CD55 + 成纤维细胞具有较高的增殖率和较低的胶原蛋白表达，表明白血病发生过程中细胞外基质重塑。重要的是，共培养测定发现白血病前期 CD55 + 成纤维细胞显著扩增了 pLSCs 而不是 nHSC。总之，我们已经确定了一种独特的 pBMM 和一种新的 CD55 + 成纤维细胞群，该种群在 pBMM 中扩增，促进 pLSCs 优于 nHSCs。