Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells.
Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells.
复制标题
DOI：
10.1002/stem.2208
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Dunbar CE
中科院分区：
文献类型：
--
作者：
Glait-Santar C;Desmond R;Feng X;Bat T;Chen J;Heuston E;Mizukawa B;Mulloy JC;Bodine DM;Larochelle A;Dunbar CE
造血干细胞和祖细胞（HSPC）位于一个专门的小生境，调节其增殖能力和命运。越来越多的证据表明，骨髓小生境在控制白血病细胞行为方面具有相似的作用，然而，正常HSC和白血病细胞是否驻留在同一骨髓小生境中或在功能上竞争同一骨髓小生境尚不清楚。我们在竞争性再增殖模型中使用MLL-AF 9小鼠急性髓性白血病来研究正常HSPC和白血病细胞是否在功能上竞争相同的骨髓小生境。将固定数量的MLL-AF 9细胞与增加剂量的正常同系全骨髓（WBM）或纯化的HSPC（LSK）混合移植到受辐射的受体小鼠中。在多个独立实验中，与正常WBM或正常LSK细胞的剂量增加成比例，生存率显著增加，白血病进展延迟，研究的所有剂量的WBM或LSK细胞均高于在不存在白血病的情况下快速和完全造血重建的阈值。共聚焦显微镜检查显示白血病细胞或正常造血细胞的巢，但不是两者都在骨髓邻近骨内膜。移植后早期，接受较低剂量LSK的动物的白血病细胞比接受较高剂量的动物更活跃地循环。这些结果表明，正常HSPC和AML细胞竞争相同的功能小生境。小生境的操作可能影响抗白血病治疗的反应，正常HSPC的数量可能影响白血病结局，为干细胞移植背景下的细胞剂量方法提供信息。
Hematopoietic stem and progenitor cells (HSPC) reside in a specialized niche that regulates their proliferative capacity and their fate. There is increasing evidence for similar roles of marrow niches on controlling the behavior of leukemic cells, however whether normal HSC and leukemic cells reside in or functionally compete for the same marrow niche is unclear. We used the MLL-AF9 murine acute myeloid leukemia in a competitive repopulation model to investigate whether normal HSPC and leukemic cells functionally compete for the same marrow niches. Irradiated recipient mice were transplanted with fixed numbers of MLL-AF9 cells mixed with increasing doses of normal syngeneic whole bone marrow (WBM) or with purified HSPC (LSK). Survival was significantly increased and leukemic progression was delayed proportional to increasing doses of normal WBM or normal LSK cells in multiple independent experiments, with all doses of WBM or LSK cells studied above the threshold for rapid and complete hematopoietic reconstitution in the absence of leukemia. Confocal microscopy demonstrated nests of either leukemic cells or normal hematopoietic cells but not both in the marrow adjacent to endosteum. Early following transplantation, leukemic cells from animals receiving lower LSK doses were cycling more actively than in those receiving higher doses. These results suggest that normal HSPC and AML cells compete for the same functional niche. Manipulation of the niche could impact on response to anti-leukemic therapies, and the numbers of normal HSPC could impact on leukemia outcome, informing approaches to cell dose in the context of stem cell transplantation.