CXCR7: a new SDF-1-binding receptor in contrast to normal CD34(+) progenitors is functional and is expressed at higher level in human malignant hematopoietic cells

CXCR7 was identified as another stromal-derived factor-1 (SDF-1)-binding receptor that also binds the interferon-inducible T-cell chemoattractant (I-TAC), and we became interested in its potential role in migration/adhesion of normal hematopoietic stem/progenitor cells (HSPCs) as well as selected leukemia cell lines. To address this normal human bone marrow-, umbilical cord blood-, and mobilized peripheral blood-derived cells as well as 16 selected human leukemic cell lines were phenotyped for CXCR7 expression. The expression of CXCR7 in hematopoietic cell lines was analyzed at transcriptional level. The biologic significance of CXCR7 expression was subsequently tested in signal transduction studies as well as in in vitro proliferation and chemotactic assays. We noted that CXCR7 is expressed at very low levels (approximately 3-6%) in normal human CD34(+) cells isolated from bone marrow, umbilical cord blood, and mobilized peripheral blood. More importantly, when we employed I-TAC, which activates CXCR7, but not CXCR4, we did not observe any chemotactic responsiveness in human clonogenic progenitors. As expected, I-TAC also did not affect clonogenic growth of human CD34(+) cells. In contrast, functional CXCR7, whose expression is regulated in an NF-κΒ-dependent manner, as we report here, is highly expressed in several human myeloid malignant cell lines. I-TAC-induced activation of CXCR7 in human hematopoietic cell lines leads to phosphorylation of MAPKp42/44 and Akt, and enhanced cell adhesion and slightly cell migration. In conclusion, CXCR7 is expressed at very low level on normal human HSPCs and does not play a direct role in their proliferation or slightly cell migration; however, in contrast, it is involved in trafficking/adhesion of human leukemic cells.