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Analysis of the mechanism of adhesion of precursor-B acute lymphoblastic
leukemia cells to bone marrow fibroblasts
K Bradstock, V Makrynikola, A Bianchi and K Byth
Haematology Department, Westmead Hospital, New South Wales, Australia.
Normal B lymphopoiesis is dependent on a close relationship between B- cell
precursors and the bone marrow (BM) microenvironment. To further understand
the mechanisms regulating the proliferation of the malignant counterpart of
B-cell precursors, namely precursor-B acute lymphoblastic leukemia (ALL),
we examined the adhesion to BM fibroblasts (BMF) of 19 cases of precursor-B
ALL using a chromium labeling assay. Eleven of 19 cases showed greater than
10% binding to BMF (range 2.3% to 54.8%, mean 19.1%). Binding was increased
approximately twofold by preincubation of BMF with tumor necrosis factor
and interleukin-4, which also resulted in upregulation of expression of
vascular cell adhesion molecule-1 (VCAM-1) on BMF. The mechanism of
attachment was investigated using murine monoclonal antibodies to leukocyte
integrins, principally the beta, integrins VLA- 4 and VLA-5, which were
demonstrated to be present on most cases by flow cytometry. Statistically
significant inhibition of adhesion was observed with antibodies to the beta
1 common subunit, VLA-4, and VLA- 5, whereas little effect was seen with
antibodies to VLA-6 or the beta 2 integrin subunit. Preincubation of
fibroblasts with an antibody to VCAM-1 (a ligand of VLA-4) inhibited
leukemic cell binding in the majority of cases, which was an effect also
observed on cytokine- stimulated BMF. However, a minority of cases, as well
as the pre-B lines NALM-6 and KM-3, showed no evidence of inhibition of
adhesion with anti-VCAM-1 antibodies. Treatment of BMF with antifibronectin
antibody alone had little effect on ALL adhesion and did not enhance the
inhibitory effect of anti-VCAM-1. These data indicate that precursor-B ALL
cells bind to BM stroma through the beta 1 integrins VLA-4 and VLA-5 and
that this effect is partly mediated by VCAM-1 on stromal cells, although
other undefined VLA ligands are also likely to be involved. Attachment of
ALL cells to stroma is likely to play a key role in regulating the survival
and growth of these cells through exposure to stromal cytokines.
Volume 82,
Issue 11,
pp. 3437-3444,
12/01/1993
Copyright © 1993 by The American Society of Hematology
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