Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; and.
Blood Adv. 2018 Jun 26;2(12):1480-1494. doi: 10.1182/bloodadvances.2017013870.
Despite increasing evidence for the involvement of bone marrow (BM) hematopoietic stem cell niche in leukemogenesis, how BM mesenchymal stem and progenitor cells (MSPCs) contribute to leukemia niche formation and progression remains unclear. Using an MLL-AF9 acute myeloid leukemia (AML) mouse model, we demonstrate dynamic alterations of BM cellular niche components, including MSPCs and endothelial cells during AML development and its association with AML engraftment. Primary patient AML cells also induced similar niche alterations in xenografted mice. AML cell infiltration in BM causes an expansion of early B-cell factor 2 (Ebf2) MSPCs with reduced expression and enhanced generation of more differentiated mesenchymal progenitor cells. Importantly, in vivo fate-mapping indicates that Ebf2 MSPCs participated in AML niche formation. Ebf2 cell deletion accelerated the AML development. These data suggest that native BM MSPCs may suppress AML. However, they can be remodeled by AML cells to form leukemic niche that might contribute to AML progression. AML induced dysregulation of hematopoietic niche factors like , , , , , and in AML BM MSPCs, which was associated with AML engraftment and partially appeared before the massive expansion of AML cells, indicating the possible involvement of the niche factors in AML progression. Our study demonstrates distinct dynamic features and roles of BM MSPCs during AML development.
尽管越来越多的证据表明骨髓（BM）造血干细胞龛在白血病发生中的作用，但 BM 间充质干细胞和祖细胞（MSPCs）如何促进白血病龛的形成和进展仍不清楚。我们使用 MLL-AF9 急性髓系白血病（AML）小鼠模型，证明了 BM 细胞生态位成分（包括 MSPCs 和内皮细胞）在 AML 发展过程中的动态变化，以及这些变化与 AML 植入的关系。原代患者 AML 细胞在异种移植小鼠中也诱导了类似的龛位改变。AML 细胞在 BM 中的浸润导致早期 B 细胞因子 2（Ebf2）MSPCs 的扩增，其表达减少，更分化的间充质祖细胞的生成增强。重要的是，体内示踪表明 Ebf2 MSPCs 参与了 AML 龛的形成。Ebf2 细胞的缺失加速了 AML 的发展。这些数据表明，天然 BM MSPCs 可能抑制 AML。然而，AML 细胞可以重塑它们，形成白血病龛，这可能有助于 AML 的进展。AML 诱导的造血龛位因子（如 、 、 、 、 、 ）在 AML BM MSPCs 中的失调与 AML 植入有关，并且部分在 AML 细胞大量扩增之前出现，表明龛位因子可能参与 AML 的进展。我们的研究表明，在 AML 发展过程中，BM MSPCs 具有独特的动态特征和作用。
