Inhibition of the SDF-1alpha-CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice.
Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T lymphotropic virus type I, and presents as an aggressive leukemia with characteristic widespread leukemic cell infiltration into visceral organs and skin. The molecular mechanisms associated with leukemic cell infiltration are poorly understood. We have used mouse models of ATL to investigate the role of chemokines in this process. Transfer of splenic lymphomatous cells from transgenic to SCID mice reproduces a leukemia and lymphoma that is histologically identical to human disease. It could be shown that lymphomatous cells exhibit specific chemotactic activity in response to stromal cell-derived factor-1alpha (SDF-1alpha). Lymphomatous cells exhibited surface expression of CXCR4, the specific receptor of SDF-1alpha. AMD3100, a CXCR4 antagonist, was found to inhibit both SDF-1alpha-induced migration and phosphorylation of extracellular signal-related kinase 1/2. Investigation of cultured cells from human ATL patients revealed identical findings. Using the SCID mouse model, it could be demonstrated that AMD3100 inhibited infiltration of lymphomatous cells into liver and lung tissues in vivo. These results demonstrate the involvement of the SDF-1alpha/CXCR4 interaction as one mechanism of leukemic cell migration and this may provide a novel target as part of combination therapy for ATL.
Kawaguchi
Akira
A
Department of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan.
Orba
Yasuko
Y
Kimura
Takashi
T
Iha
Hidekatsu
H
Ogata
Masao
M
Tsuji
Takahiro
T
Ainai
Akira
A
Sata
Tetsutaro
T
Okamoto
Takashi
T
Hall
William W
WW
Sawa
Hirofumi
H
Hasegawa
Hideki
H
D000328:Adult; D000368:Aged; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000080027:Cyclams; D005260:Female; D016356:Gene Products, tax / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D016356:Gene Products, tax; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C088327:plerixafor