Year: 2019
Type: dissertation
Abstract: Acute myeloid leukemia (AML) is a highly heterogeneous and growth factor-dependent disease. Colony stimulating factor 1 (CSF1) is a cytokine produced by bone marrow (BM) stromal cells that directs the differentiation and growth of myeloid cell precursors into monocytes and macrophages. Human CSF1 (hCSF1) exists as a soluble/secreted (hCSF1-sol), and a transmembrane (hCSF1-mem) isoform. CSF1 acts on the CSF1 receptor (CSF1R), which is expressed on mononuclear phagocytic cells. In this study, the CSF1-CSF1R ligand-receptor pair was investigated in the context of AML-stromal cell interactions. Analysis of cell surface CSF1R protein levels revealed that a subset of AML patient samples express high levels of CSF1R (CSF1Rhigh), and that these patients have shorter overall survival (OS) times compared to patients with low CSF1R expression (CSF1Rlow). In examining the CSF1-CSF1R interaction experimentally, the long-term growth and survival of CSF1Rhigh AML cells was supported by MS-5 stromal cells expressing human CSF1 (hCSF1) in co-culture experiments. MS-5 cells expressing the membrane-bound form of CSF1 (hCSF1-mem) in particular led to significant increases in AML cell numbers and adhesion to stroma, compared to cells co-cultured with MS-5 empty vector (EV) or hCSF1-sol cells. Co-culture of AML cells with MS-5 hCSF1-mem cells led to activation of mTOR signaling in AML cells as observed through increases in pS6, increased expression of the hematopoietic stem cell markers CD34 and c-Kit on AML cells, and distinct changes in the cytokine profiles of both AML and stromal cells. Further to this, deletion of the PDZ domain binding motif (PDBM) at the C-terminal end of CSF1 ligand in MS-5 stromal cells led to decreased stromal support of AML cells, and reduced mTOR pathway activation. The interaction between CSF1 and CSF1R mediates supportive effects between AML and stromal cells by fostering bilateral intracellular and intercellular signaling changes. As such, targeting the CSF1-CSF1R interaction may prove to be an effective therapeutic strategy to overcome and compromise the protective and supportive role of the BM niche in AML disease pathogenesis.
Source: TSpace (University of Toronto)
Author: Ayesha Rashid
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3141214291