Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. Despite major improvements in cure rates, significant numbers of patients relapse and their prognosis remains dismal. ALL originates in the bone marrow and cell-cell interactions in this microenvironment can alter disease progression and treatment efficacy.
Connective tissue growth factor (CTGF) is significantly up-regulated in approximately 75% of pre-B ALL specimens. CTGF is a secreted protein with functions in mesenchymal stem cell differentiation, fibrosis and cancer, such as neo-vascularisation, migration, and proliferation. The role of CTGF in ALL is currently unknown. Addition of CTGF to two bone marrow stromal cell lines enhanced their proliferation. Using lentiviral technology, we generated patient-derived pre-B ALL cell lines PER-278 and PER-371 that in each case secrete high or low levels of CTGF. These cells did not show altered proliferation in vitro. However, xenograft NOD/SCID mice transplanted with high CTGF-expressing PER-371 cells showed accelerated leukaemia development compared to low CTGF-expressing PER-371 xenografts (median survival 70 vs 89 days; p=0.03). To examine the interaction of leukaemia and stromal cells, we measured adhesion of pre-B ALL cells to stromal cells in vitro, which was significantly increased when stromal cells were pre-incubated with exogenous CTGF. Moreover, adhesion protected leukaemia cells from toxicity by two drugs, vincristine and cytosine arabinoside. Gene expression profiling of bone marrow stromal cells incubated with CTGF revealed significant changes to genes involved in extracellular matrix production, cell motility and cell cycle. Together, this data demonstrates an important role for CTGF in mediating ALL- stromal cell interactions. We propose that CTGF-induced effects contribute to both leukaemogenesis and adhesion-mediated drug resistance. Current studies aim to delineate these interactions in vivo with the goal of better understanding disease development and therapy-resistance in children with ALL.