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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2107-2113
IMMUNOBIOLOGY
Leukemic target susceptibility to natural killer
cytotoxicity: relationship with BCR-ABL expression
Frédéric Baron,
Ali G. Turhan,
Julien Giron-Michel,
Bruno Azzarone,
Mohamed Bentires-Alj,
Vincent Bours,
Jean Henri Bourhis,
Salem Chouaib, and
Anne Caignard
From INSERM 487, Laboratoire de thérapie
cellulaire, Institut Gustave Roussy, Villejuif, France; INSERM 506 Hôpital Paul Brousse, Villejuif, France; and Laboratoire de
Chimie Médicale et d'Oncologie Médicale, Université
de Liège, Belgique.
Chronic myeloid leukemia is a clonal myeloproliferative expansion
of transformed primitive hematopoietic progenitor cells characterized
by high-level expression of BCR-ABL chimeric gene, which induces growth
factor independence. However, the influence of BCR-ABL expression on
cell-mediated cytotoxicity is poorly understood. In the present study,
we asked whether BCR-ABL expression interferes with leukemic target
sensitivity to natural killer (NK) cell cytolysis. Our approach was
based on the use of 2 BCR-ABL transfectants of the pluripotent
hematopoietic cell line UT-7 expressing low (UT-7/E8, UT-7/G6) and high
(UT-7/9) levels of BCR-ABL. As effector cells, we used
CD56bright, CD16 , CD2 NK cells
differentiated in vitro from CD34 cord blood progenitors. We
demonstrated that BCR-ABL transfectants UT-7/9 were lysed by NK cells
with a higher efficiency than parental and low UT-7/E8.1 and UT-7/G6
transfectants. This enhanced susceptibility to lysis correlated with an
increase in expression of intercellular adhesion molecule 1 (ICAM-1) by
target cells. Treatment of UT-7/9 cells by STI571 (a specific inhibitor
of the abl kinase) resulted in a decrease in NK susceptibility to lysis
and ICAM-1 down-regulation in target cells. Furthermore, the
constitutive activation of nuclear factor- B (NF-B) detected in
BCR-ABL transfectant UT-7/9, was significantly attenuated when cells
were treated by STI571. Interestingly, inhibition of NF-B activation
by BAY11-67082 (a specific NF-B inhibitor) resulted in
down-regulation of ICAM-1 expression and a subsequent decrease in
NK-induced killing of UT-7/9 transfectants. Our results show that
oncogenic transformation by BCR-ABL may increase susceptibility of
leukemic progenitors to NK cell cytotoxicity by a mechanism involving
overexpression of ICAM-1 as a consequence of NF-B activation.
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