CSF-1 plays a role in regulating innate immune responses promoting macrophage growth and differentiation. We hypothesized CSF-1 may also play a role in growth and progression of Acute Myeloid Leukaemia (AML). Our aim is to investigate the role of CSF-1 in survival and chemo-resistance of leukaemia stem and progenitor cells (LSPC). Blocking CSF-1R signalling in LSPC may dampen leukaemia survival in vitro and delay leukaemia progression in vivo.
AML was induced in mice by injecting murine Haematopoietic Stem and Progenitor Cells (HSPC) transduced with either MLL-AF9 or AML1- ETO fusion oncogenes for the development of either monomyelocytic or granulocytic leukaemia respectively. We found CSF-1R expressed on these AML cells, possibly that CSF-1 provide supportive microenvironment for leukemic growth. To identify whether CSF-1 in the bone marrow (BM) niche is essential for LSPC growth, we harvested normal or leukaemic blasts from BM for Long-Term Culture-Initiating-Cell (LT-CIC) assays in vitro. LSPC or HSPC cells were co-cultured with OP9 (produce non-functional CSF-1). We found wild-type HSPC were able to proliferate, survive and produce LT-CIC in the absence of niche-provided CSF-1, however AML blasts could not, unless rescued by addition of recombinant CSF-1 (100 ng/mL). Together these data suggest CSF-1 signalling may be critical for AML LSPC but not normal HSPC.
Next we investigated in mice whether therapeutic CSF-1 blockade could similarly dampen AML survival or progression in vivo. Cohorts of mice were injected with AML, 7 days later administered CSF-1 antagonist (GW2580, 160mg/kg) or vehicle control. Leukaemia progression was tracked by bioluminescence and testbleeds (GFP+ leukaemia blasts). We found therapeutic blockade of CSF-1 significantly reduced tumour burden significantly extended the duration of overall mouse survival (P<0.005, n= 8 mice/ group).
Together these studies suggest therapeutic CSF-1 blockade may show promise as an adjunct therapy to help reduce tumour burden and improve success of AML leukaemia therapies.