Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging
Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging
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DOI：
10.1111/imcb.12216
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发表时间：
2019-02-01
影响因子：
4
通讯作者：
Lo Celso, Cristina
中科院分区：
文献类型：
--
作者：
Duarte, Delfim;Amarteifio, Saoirse;Lo Celso, Cristina
大多数急性髓性白血病（AML）患者对常规化疗的反应较差。化疗耐药细胞的存活被认为取决于白血病-骨髓（BM）微环境相互作用，这一点尚未得到很好的理解。CXCL 12/CXCR 4轴已被提出支持AML生长，但未在单个AML细胞水平上进行研究。我们最近发现T细胞急性淋巴细胞白血病（T-ALL）细胞在BM中具有高度运动性;然而，AML细胞在BM中迁移的特征仍不明确。在这里，我们使用小鼠颅骨BM的高分辨率双光子和共聚焦活体显微镜和完善的MLL-AF 9驱动的AML小鼠模型，表征了AML细胞的体内迁移行为及其对化疗和CXCR 4拮抗作用的反应。我们使用Notch 1驱动的T-ALL模型作为基准比较，并使用AMD 3100进行CXCR 4拮抗实验。我们发现AML细胞是迁移性的，与T-ALL相反，化疗耐药的AML细胞变得不那么活跃。此外，与T-ALL相反，扩增和化疗耐药AML细胞的体内探索行为不受AMD 3100的影响。这些结果扩展了我们对AML细胞-BM微环境相互作用的理解，突出了不同谱系白血病的独特特征。
The majority of acute myeloid leukemia (AML) patients have a poor response to conventional chemotherapy. The survival of chemoresistant cells is thought to depend on leukemia-bone marrow (BM) microenvironment interactions, which are not well understood. The CXCL12/CXCR4 axis has been proposed to support AML growth but was not studied at the single AML cell level. We recently showed that T-cell acute lymphoblastic leukemia (T-ALL) cells are highly motile in the BM; however, the characteristics of AML cell migration within the BM remain undefined. Here, we characterize the in vivo migratory behavior of AML cells and their response to chemotherapy and CXCR4 antagonism, using high-resolution 2-photon and confocal intravital microscopy of mouse calvarium BM and the well-established MLL-AF9-driven AML mouse model. We used the Notch1-driven T-ALL model as a benchmark comparison and AMD3100 for CXCR4 antagonism experiments. We show that AML cells are migratory, and in contrast with T-ALL, chemoresistant AML cells become less motile. Moreover, and in contrast with T-ALL, the in vivo exploratory behavior of expanding and chemoresistant AML cells is unaffected by AMD3100. These results expand our understanding of AML cells-BM microenvironment interactions, highlighting unique traits of leukemia of different lineages.