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Title: Defining key molecules in a myeloma cell niche
Author: Paton-Hough, Julia
ISNI:       0000 0004 5356 5574
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Multiple myeloma is an incurable B cell malignancy characterised by the expansion of malignant plasma cells in the bone marrow. It has been suggested that during initial colonisation of bone and possibly during therapy, some myeloma cells may occupy a bone marrow niche similar to that inhabited by haemopoietic stem cells. Haemopoietic stem cells residing in BM niches adhere to osteoblastic cells via a series of molecules that promote haemopoietic stem cell quiescence. Therefore, we hypothesise that myeloma cells express the same molecules as haemopoietic stem cells, chemokine C-X-C-motif-receptor 4, notch-1, tyrosine kinase-2 and n-cadherin, which interact with their complementary ligands expressed by osteoblastic cells, chemokine C-X-C-motif-ligand 12, jagged-1, angiopoietin-1 and n-cadherin. These interactions may result in myeloma cell adhesion to an osteoblastic niche, resulting in myeloma cell dormancy. The aims of these studies were to determine the expression of haemopoietic stem cell niche molecules and ligands by murine myeloma cell lines and osteoblastic cells and to determine the role of one of the key molecules in vitro and in vivo. 5T33MMvt and 5TGM1 cells expressed the haemopoietic stem cell niche molecules; chemokine C-X-C-motif-receptor 4, notch-1, tyrosine kinase-2 and n-cadherin and the MC3T3-E1 cells and primary osteoblast lineage cells expressed the ligands chemokine C-X-C-ligand 12, jagged-1, angiopoietin-1 and n-cadherin. Knock-down of n-cadherin was achieved in the 5TGM1 cells, with 71% gene and 75% protein reduction. 5TGM1 n-cadherin knock-down cell attachment to primary osteoblast lineage cells was reduced in vitro, though this did not reach significance. Mice injected with 5TGM1 n-cadherin knock-down cells had significantly less tumour in vivo compared to controls. In conclusion, murine myeloma cells expressed the same repertoire of molecules as haemopoietic stem cells and osteoblastic cells expressed their complementary ligands. Knock-down of one of these key molecules, n-cadherin, did not significantly inhibit myeloma cell attachment to primary osteoblasts in vitro but potentially impaired tumour growth in vivo. Further experiments are required to confirm this.
Supervisor: Eaton, C. L. ; Lawson, M. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available