3174 – TANDEM MYELOID GROWTH FACTOR TREATMENT ENHANCED THE TOTAL HAEMATOPOIETIC STEM CELL (HSC) POOL AND MAGNITUDE OF HSC MOBILISATION

Autologous HSC transplant is a common therapeutic strategy for some haematological malignancies but is unachievable in up to 40% of cases due to insufficient mobilisation of HSCs for successful transplantation. The monocyte-macrophage colony stimulating factor-1 (CSF1) improves HSC transplantation outcomes in preclinical models and clinical trials, but the underlying mechanism of CSF1 induced benefit is unclear. BM macrophages are a key component of the HSC niches and a primary target of granulocyte colony-stimulating factor (G-CSF) induced HSC mobilisation. We examined CSF1 impacts on HSC frequency using a modified CSF1-Fc molecule that has improved drug qualities. Haematopoietic progenitor cells (HPC), but not HSCs or multipotent progenitors (MPP), expressed the CSF1 receptor. Acute CSF1-Fc treatment (4 x daily injection) induced a robust myeloproliferative response that was evident 1 week post the initial injection. At this time, BM HSCs (17 fold) and MPP (19 fold), but not HPC, were significantly reduced. However, at 2 weeks post the first CSF1-Fc injection, after the myeloproliferative event had resolved, the overall pool of HSCs in BM (1.6 fold), and unexpectedly spleen (9.2 fold), was significantly elevated compared to controls. A mobilising regimen of G-CSF started at 2 weeks post CSF1-Fc treatment enhanced HSC mobilisation (2.5 fold) into blood when compared to mice treated with G-CSF only. This increase in mobilised HSCs was verified via competitive secondary transplantation. The data suggest that CSF1 has complex indirect effects on HSCs to increase HSC frequency and promote formation of extramedullary HSC niches. CSF1-induced increased in the total HSC pool may contribute to the reported improvement in transplantation outcomes associated with CSF1 therapy and reveals a novel strategy to increase HSCs prior to mobilisation.