title: High expression of connective tissue growth factor accelerates dissemination of leukaemia.
abstract: To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Wells
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Howlett
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: H M
authors.initials: HM
authors.lastname: Halse
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Heng
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Ford
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: L C
authors.initials: LC
authors.lastname: Cheung
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: A L
authors.initials: AL
authors.lastname: Samuels
authors.affiliation: Princess Margaret Hospital for Children, Perth, Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Crook
authors.affiliation: Princess Margaret Hospital for Children, Perth, Western Australia, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Charles
authors.affiliation: School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.|Princess Margaret Hospital for Children, Perth, Western Australia, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Cole
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: U R
authors.initials: UR
authors.lastname: Kees
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor