title: CD45 regulates homing and engraftment of immature normal and leukemic human cells in transplanted immunodeficient mice.
abstract: Bone marrow homing and engraftment by clinically transplanted hematopoietic stem and progenitor cells is a complex process that is not fully understood. We report that the pan-leukocyte CD45 phosphatase plays an essential role in trafficking and repopulation of the bone marrow by immature human CD34(+) cells and leukemic cells in transplanted nonobese diabetic severe combined immunodeficient mice. Inhibiting CD45 function by blocking antibodies or a CD45 inhibitor impaired the motility of both normal and leukemic human cells. Blocking CD45 inhibited homing and repopulation by immature human CD34(+) cells as well as homing of primary patient leukemic cells. In addition, CD45 inhibition negatively affected development of hematopoietic progenitors in vitro and their recovery in transplanted recipients in vivo, revealing the central role of CD45 in the regulation of hematopoiesis. Moreover, CD45 blockage induced a hyperadhesive phenotype in immature human progenitor cells as well as in murine leukocytes, leading to their defective adhesion interactions with endothelial cells. This phenotype was further manifested by the ability of CD45 blockage to prevent breakdown of adhesion interactions in the BM, which inhibited murine progenitor mobilization. The substantial effects of a direct CD45 inhibition point at its essential roles in cell trafficking, including murine progenitor cell mobilization and both normal immature and leukemic human hematopoietic cells as well as regulation of hematopoiesis and engraftment potential.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.forename: Kfir
authors.initials: K
authors.lastname: Lapid
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Kalchenko
authors.forename: Abraham
authors.initials: A
authors.lastname: Avigdor
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003114:Colony-Forming Units Assay; D036101:Cord Blood Stem Cell Transplantation; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells / Q000637:transplantation; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011828:Radiation Chimera; D014407:Tumor Cells, Cultured / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D016179:Granulocyte Colony-Stimulating Factor; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse