High Expression of Connective Tissue Growth Factor (CTGF/CCN2) Modifies the Bone Marrow Microenvironment and Accelerates Dissemination of Leukaemia

International cooperative clinical trials for childhood leukaemia have successfully increased the overall cure rate to over 85%. The current focus is to improve outcome for patients through discovery of less toxic targeted therapies. The bone marrow microenvironment plays an important role in leukaemogenesis and minimal residual disease, facilitating drug resistance and disease relapse. A target not yet explored in leukaemia is the extracellular matrix (ECM).

Our laboratory aims to identify ECM-associated drug targets in B-cell precursor acute lymphoblastic leukaemia (pre-B ALL). We identified connective tissue growth factor (CTGF/CCN2) as over-expressed in approximately 75% of patient samples in childhood pre-B ALL (Boag et al. Leukemia, 2006,20:1731; Boag et al. BJH 2007,138:740). CTGF is a matricellular protein and is significantly involved in aggressive cancers (Wells et al. Int J Cancer 2015,137:504; Wells et al. J Cell Commun Signal. 2015 Epub May 31). To test whether CTGF plays a functional role in disease outcome we engrafted NOD/SCID mice with pre-B ALL cells that were lentivirally transduced to express increased or reduced levels of CTGF. Increased CTGF expression in PER-371 cells reduced survival by 11 days (p=0.003). Reduced CTGF expression extended mean survival by 14 days (p<0.0002) in PER-371, and 38 days (p=0.0015) in PER-377 xenografted mice. Increased CTGF expression was associated with increased lysyl oxidase (LOX) expression in non-leukaemic cells at an early stage of disease development. At later stages of disease development increased CTGF was associated with increased ECM deposition.

Further studies are in progress to explore targeting the overexpressed CTGF and LOX proteins in the bone marrow, shown to be associated with increased ECM synthesis and an accelerated spread of disease.