MIM REGULATES THE TRAFFICKING OF BONE MARROW CELLS VIA MODULATING SURFACE EXPRESSION OF CXCR4

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 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 2 to 5-fold 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 wild type mice. MIM(-/-) mice had also a higher level of SDF-1 in the circulation. Our data highlighted an unprecedented role of MIM in the homoeostasis of BM cells, including HSPCs, through modulation of the CXCR4/SDF-1 axis and interactions of BM leukocytes with their microenvironments.