Zhan T, Cao C, Li L, Gu N, Civin C I, Zhan X
Department of Pathology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Leukemia. 2016 Jun;30(6):1327-34. doi: 10.1038/leu.2016.39. Epub 2016 Feb 29.
Missing in metastasis (MIM) is abundantly expressed in hematopoietic cells. Here we characterized the impact of MIM deficiency on murine bone marrow (BM) cells. Although MIM(-/-) cells proliferated similarly to wild type (WT), they exhibited stronger response to chemokine stromal-derived factor 1 (SDF-1), increase in surface expression of CXCR4, impaired CXCR4 internalization and constitutive activation of Rac, Cdc42 and p38. Transplantation of MIM(-/-) BM cells into lethally irradiated mice showed enhanced homing to BM, which was abolished when mice were pretreated with a p38 antagonist. Interestingly, MIM(-/-) BM cells, including hematopoietic stem and progenitor cells (HSPCs), showed two- to fivefold increase in mobilization into the peripheral blood upon treatment with AMD3100. In vitro, MIM(-/-) leukocytes were susceptible to AMD3100 and maintained increased response to AMD3100 for mobilization even after transfer into WT mice. MIM(-/-) mice had also a higher level of SDF-1 in the circulation. Our data highlighted an unprecedented role of MIM in the homeostasis of BM cells, including HSPCs, through modulation of the CXCR4/SDF-1 axis and interactions of BM leukocytes with their microenvironments.
转移缺失蛋白（MIM）在造血细胞中大量表达。在此，我们对MIM缺陷对小鼠骨髓（BM）细胞的影响进行了表征。尽管MIM基因敲除（MIM(-/-)）细胞的增殖与野生型（WT）相似，但它们对趋化因子基质衍生因子1（SDF-1）表现出更强的反应，CXCR4的表面表达增加，CXCR4内化受损，并且Rac、Cdc42和p38呈组成性激活。将MIM(-/-)骨髓细胞移植到接受致死性照射的小鼠体内，显示出归巢至骨髓的能力增强，而当小鼠用p38拮抗剂预处理时，这种增强作用被消除。有趣的是，在用AMD3100处理后，包括造血干细胞和祖细胞（HSPCs）在内的MIM(-/-)骨髓细胞向外周血的动员增加了2至5倍。在体外，MIM(-/-)白细胞对AMD3100敏感，并且即使转移到WT小鼠体内后，对AMD3100的动员反应仍保持增强。MIM(-/-)小鼠循环中的SDF-1水平也更高。我们的数据突出了MIM在通过调节CXCR4/SDF-1轴以及骨髓白细胞与其微环境的相互作用来维持包括HSPCs在内的骨髓细胞稳态方面前所未有的作用。
