Abstract 4123: Investigation of growth factor signaling through macrophage colony stimulating factor (CSF-1) and its receptor (FMS) in the bone marrow stromal microenvironment in acute myeloid leukemia (AML).

Abstract

Abstract Acute myeloid leukemia (AML) is a highly heterogeneous and growth factor-dependent disease of the bone marrow. The bone marrow stromal microenvironment plays a critical role in providing growth and survival signals. hFMS, the human homologue of the Feline (McDonough strain) Sarcoma virus oncogene, also known as macrophage colony stimulating factor 1 receptor (CSF1R, FMS, CD115) is a tyrosine kinase receptor found on mononuclear phagocytes that promotes their growth and differentiation. The human macrophage CSF-1 ligand (MCSF-1, CSF-1) produced by supporting cells in the bone marrow acts on FMS. CSF-1 has a full length secreted isoform v1 and a membrane-bound isoform v3. Upon activation, FMS modulates the activity of important effectors of growth and survival pathways such as the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositol-3 kinase (PI3K)/Akt pathways, respectively. There is a variable association of Fms with the stem cell marker CD34 on AML cells and this suggests different structures within an AML hierarchy. To better understand stromal cell interactions mediated by the CSF-1/FMS axis and examine the high engraftment failures of AML human samples in mice, AML cells were grown on murine stromal cells that were ‘humanized’ through lentiviral-mediated introduction of human CSF-1. The soluble v1 and membrane-bound v3 isoforms of CSF-1 were investigated. We found that stroma-presented CSF-1 effectively supports the growth of leukemic cells in short and long-term growth cultures, with the v3 CSF-1 variant sustaining better growth than v1. Interestingly the FMS-(low)/CD34+ subpopulation displayed significantly better growth on stroma compared to the FMS+ populations. Eventually this subpopulation gave rise to FMS+ cells, suggesting that it may harbor stem or initiating properties. In interrogating molecular signaling events induced by the CSF-1/FMS interaction, we found that the membrane-bound v3 isoform leads to increases in phosphorylation of effectors of the MAPK and PI3k/Akt pathways, namely Akt, p70S6K and 4E-BP1, whereas the v1 variant does not elicit such signals as robustly in leukemic cells grown on stroma. Taken together, this indicates that the manner in which the ligand is presented (soluble vs. membrane-bound) impacts the growth, survival and molecular signaling arising from the leukemic-stromal cell interaction. Future work will involve generation of gene and protein expression profiles of leukemic and stromal cells after grown in co-culture in aims of identifying targets induced by the soluble vs. membrane-bound forms of CSF-1. Particular identification of druggable targets in both leukemic and stromal cell compartments will allow for the design of therapeutic strategies to interfere with leukemic-stromal cell interactions driven by the CSF-1/FMS axis. Citation Format: Ayesha Rashid, Mohamed Fateen, Aaron Schimmer, Mark Minden. Investigation of growth factor signaling through macrophage colony stimulating factor (CSF-1) and its receptor (FMS) in the bone marrow stromal microenvironment in acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4123. doi:10.1158/1538-7445.AM2013-4123