title: Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1.
abstract: Chronic myelogenous leukemia (CML), a malignant myeloproliferative disorder originating from a pluripotent stem cell expressing the bcr-abl oncogene, is characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow (BM) into the circulation. Moreover, immature CD34+ CML cells have lower adhesion to stromal cells and fibronectin as well as lower engraftment potential in severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID mice than normal CD34+ cells. We report in this study that leukemic Philadelphia chromosome-positive (Ph+)CD34+ cells from newly diagnosed CML patients that express the chemokine receptor CXCR4 migrate in response to stromal-derived factor-1 (SDF-1). However, normal Ph-CD34+CXCR4+ cells derived from the same patient have significantly higher migration levels toward SDF-1. In contrast to their transwell migration potential, the SDF-1-mediated integrin-dependent polarization and migration of the Ph+CD34+CXCR4+ cells through extracellular matrix-like gels were significantly lower than for normal cells. Concomitantly, binding of these cells to vascular cell adhesion molecule-1 or fibronectin, in the presence of SDF-1, was also substantially lower. These findings suggest a major role for SDF-1-mediated, integrin-dependent BM retention of Ph+CD34+ cells.
authors: Hadassah University Hospital, Gene Therapy Institutem, Jerusalem, Israel. peled@hadassah.org.il
authors: Amnon
authors: A
authors: Peled
authors: Izhar
authors: I
authors: Hardan
authors: Luba
authors: L
authors: Trakhtenbrot
authors: Eyal
authors: E
authors: Gur
authors: Michal
authors: M
authors: Magid
authors: Merav
authors: M
authors: Darash-Yahana
authors: Ninette
authors: N
authors: Cohen
authors: Valentin
authors: V
authors: Grabovsky
authors: Suzana
authors: S
authors: Franitza
authors: Orit
authors: O
authors: Kollet
authors: Ofer
authors: O
authors: Lider
authors: Ronen
authors: R
authors: Alon
authors: Gideon
authors: G
authors: Rechavi
authors: Tsvee
authors: T
authors: Lapidot
mesh_terms: D018952:Antigens, CD34; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood*; D010677:Philadelphia Chromosome; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D016029:Receptors, Very Late Antigen / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D016023:Integrins; D019718:Receptors, CXCR4; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen