title: CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice.
abstract: The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m(null) mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Tavor
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petit
authors.forename: Svetlana
authors.initials: S
authors.lastname: Porozov
authors.forename: Abraham
authors.initials: A
authors.lastname: Avigdor
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.forename: Leonor
authors.initials: L
authors.lastname: Leider-Trejo
authors.forename: Noga
authors.initials: N
authors.lastname: Shemtov
authors.forename: Varda
authors.initials: V
authors.lastname: Deutsch
authors.forename: Ella
authors.initials: E
authors.lastname: Naparstek
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000637:transplantation*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D000906:Antibodies; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4