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Inhibition of BCR-ABL Expression With Antisense Oligodeoxynucleotides
Restores  1 Integrin-Mediated Adhesion and Proliferation
Inhibition in Chronic Myelogenous Leukemia Hematopoietic Progenitors
Ravi Bhatia and
Catherine M. Verfaillie
From the Department of Hematology and Bone Marrow Transplantation,
City of Hope National Medical Center, Duarte, CA; and the Division of
Hematology, Department of Medicine, University of Minnesota,
Minneapolis.
Chronic myelogenous leukemia (CML) is characterized by the
continuous proliferation and abnormal circulation of malignant hematopoietic progenitors. This may be related to the unresponsiveness of CML progenitors to  1 integrin adhesion receptor-mediated
inhibition of progenitor proliferation by the marrow microenvironment.
In hematopoietic cell lines, the BCR-ABL oncogene product,
p210BCR-ABL, interacts with a variety of cytoskeletal
elements important for normal integrin signaling. We studied the role
of p210BCR-ABL in abnormal integrin function in CML by
evaluating the effect of inhibition of BCR-ABL expression with
antisense oligodeoxynucleotides (AS-ODNs) on integrin-mediated adhesion
and proliferation inhibition of malignant primary progenitors from CML
marrow. Preincubation of CML CD34+HLA-DR+
(DR+) cells with breakpoint-specific AS-ODNs
significantly increased adhesion of CML progenitors to stroma and
fibronectin (FN). Pretreatment with breakpoint-specific ODNs also
resulted in significant inhibition of CML progenitor proliferation
after ligand or antibody-mediated 1 integrin engagement.
Breakpoint-specific ODNs were significantly more effective in restoring
CML progenitor adhesion and proliferation inhibition than control ODNs.
BCR-ABL mRNA and p210BCR-ABL levels in CML
CD34+ cells were significantly reduced after incubation
with breakpoint-specific AS-ODN. These studies indicate a role for
BCR-ABL in abnormal circulation and defective integrin-dependent
microenvironmental regulation of proliferation of CML hematopoietic
progenitors.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3414-3422
© 1998 by The American Society of Hematology.
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