Open AccessCCN3: a key growth regulator in Chronic Myeloid Leukaemia
Author(s) -
McCallum Lynn,
Lu Wanhua,
Price Susan,
Lazar Noureddine,
Perbal Bernard,
Irvine Alexandra E.
Publication year - 2009
Publication title -
journal of cell communication and signaling
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-009-0058-2
Subject(s) - imatinib , cancer research , k562 cells , regulator , myeloid leukemia , tyrosine kinase , cell growth , haematopoiesis , progenitor cell , transfection , tyrosine kinase inhibitor , stem cell , myeloid , imatinib mesylate , apoptosis , biology , microbiology and biotechnology , medicine , immunology , leukemia , signal transduction , cell culture , cancer , gene , biochemistry , genetics
Chronic Myeloid Leukaemia (CML) is characterized by expression of the constitutively active Bcr‐Abl tyrosine kinase. We have shown previously that the negative growth regulator, CCN3, is down‐regulated as a result of Bcr‐Abl kinase activity and that CCN3 has a reciprocal relationship of expression with BCR‐ABL. We now show that CCN3 confers growth regulation in CML cells by causing growth inhibition and regaining sensitivity to the induction of apoptosis. The mode of CCN3 induced growth regulation was investigated in K562 CML cells using gene transfection and treatment with recombinant CCN3. Both strategies showed CCN3 regulated CML cell growth by reducing colony formation capacity, increasing apoptosis and reducing ERK phosphorylation. K562 cells stably transfected to express CCN3 showed enhanced apoptosis in response to treatment with the tyrosine kinase inhibitor, imatinib. Whilst CCN3 expression was low or undetectable in CML stem cells, primary CD34+ CML progenitors were responsive to treatment with recombinant CCN3. This study shows that CCN3 is an important growth regulator in haematopoiesis, abrogation of CCN3 expression enhances BCR‐ABL dependent leukaemogenesis. CCN3 restores growth regulation, regains sensitivity to the induction of apoptosis and enhances imatinib cell kill in CML cells. CCN3 may provide an additional therapeutic strategy in the management of CML.