Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1.
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.
Peled
Amnon
A
Hadassah University Hospital, Gene Therapy Institutem, Jerusalem, Israel. peled@hadassah.org.il
Hardan
Izhar
I
Trakhtenbrot
Luba
L
Gur
Eyal
E
Magid
Michal
M
Darash-Yahana
Merav
M
Cohen
Ninette
N
Grabovsky
Valentin
V
Franitza
Suzana
S
Kollet
Orit
O
Lider
Ofer
O
Alon
Ronen
R
Rechavi
Gideon
G
Lapidot
Tsvee
T
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*
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