Premium
The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia
Author(s) -
Suresh Sukanya,
McCallum Lynn,
Crawford Lisa J,
Lu Wan Hua,
Sharpe Daniel J,
Irvine Alexandra E
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4246
Subject(s) - hes1 , cancer research , k562 cells , signalling , haematopoiesis , myeloid , gene silencing , breakpoint cluster region , imatinib , microbiology and biotechnology , notch signaling pathway , biology , chemistry , myeloid leukemia , receptor , immunology , leukemia , signal transduction , stem cell , gene , genetics
Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia ( CML ) is not well established. We previously reported BCR‐ABL down‐regulation of a novel haematopoietic regulator, CCN3 , in CML ; CCN3 is a non‐canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML . In K562 cells, BCR‐ABL silencing reduced full‐length NOTCH1 ( NOTCH1‐FL ) and inhibited the cleavage of NOTCH1 intracellular domain ( NOTCH1‐ICD ), resulting in decreased expression of the NOTCH1 targets c‐ MYC and HES1 . K562 cells stably overexpressing CCN3 ( K562 / CCN3 ) or treated with recombinant CCN3 ( rCCN3 ) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1‐ICD , p < 0.05). Gamma secretase inhibitor ( GSI ), which blocks NOTCH1 signalling, reduced K562 / CCN3 colony formation but increased that of K562 /control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR‐ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML . © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.