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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1716-1723.
Prepublished online as a Blood First Edition Paper on May 2, 2006; DOI 10.1182/blood-2006-04-016113.
 Previous Article | Next Article 
Submitted April 11, 2006
Accepted April 24, 2006
A novel mechanism for BCR-ABL action: stimulated secretion
of CCN3 is involved in growth and differentiation regulation
Lynn McCallum, Susan Price, Nathalie Planque, Bernard Perbal, Andrew Pierce, Anthony D Whetton, and Alexandra E Irvine*
Department of Hematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast,UK
Laboratoire d'Oncologie Virale et Moleculaire, UFR de Biochimie, Universite Paris7-D-Diderot, Paris
Faculty of Medical and Human Sciences, University of Manchester, Christie Hospital, Manchester, UK
* Corresponding author; email: s.irvine{at}qub.ac.uk.
Chronic myeloid leukemia is characterized by the presence
of the constitutively active BCR-ABL protein tyrosine
kinase. Using a multipotent hemopoietic cell line,
FDCP-Mix, expressing BCR-ABL tyrosine kinase we
investigated the initial effects of this kinase in
primitive hematopoietic stem cells. We identified
downregulation of a novel gene, CCN3, as a direct
consequence of BCR-ABL kinase activity. CCN3 has been
reported to function as a tumor suppressor gene in solid
tumors. Northern and Western blotting plus
immunocytochemical analysis confirmed CCN3 expression is
decreased and it is tyrosine phosphorylated in BCR-ABL
kinase active FDCP-Mix cells. Decreased cellular CCN3
correlated with increased CCN3 secretion in BCR-ABL kinase
active cells. In vitro treatment of human CML cell lines
with imatinib or si-RNA directed against BCR-ABL
significantly reduced BCR-ABL whilst increasing CCN3
expression. Cells from patients responding to imatinib
showed a similar decrease in BCR-ABL and increase in
CCN3.CML CD34+ cells treated with imatinib in
vitro demonstrated increased CCN3 protein. Transfecting
CCN3 into BCR-ABL+ cells, inhibited
proliferation and decreased clonogenic potential. CCN3
plays an important role in internal and external cell
signaling pathways. Thus BCR-ABL can regulate protein
levels by governing secretion, a novel mechanism for this
tyrosine kinase.
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