title: SAMSN1 is a tumor suppressor gene in multiple myeloma.
abstract: Multiple myeloma (MM), a hematological malignancy characterized by the clonal growth of malignant plasma cells (PCs) in the bone marrow, is preceded by the benign asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Several genetic abnormalities have been identified as critical for the development of MM; however, a number of these abnormalities are also found in patients with MGUS, indicating that there are other, as yet unidentified, factors that contribute to the onset of MM disease. In this study, we identify a Samsn1 gene deletion in the 5TGM1/C57BL/KaLwRij murine model of myeloma. In addition, SAMSN1 expression is reduced in the malignant CD138+ PCs of patients with MM and this reduced expression correlates to total PC burden. We identify promoter methylation as a potential mechanism through which SAMSN1 expression is modulated in human myeloma cell lines. Notably, re-expression of Samsn1 in the 5TGM1 murine PC line resulted in complete inhibition of MM disease development in vivo and decreased proliferation in stromal cell-PC co-cultures in vitro. This is the first study to identify deletion of a key gene in the C57BL/KaLwRij mice that also displays reduced gene expression in patients with MM and is therefore likely to play an integral role in MM disease development.
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, Australia; Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Noll
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, Australia; Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Hewett
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, Australia; Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Williams
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, Australia; Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.affiliation: Acute Myeloid Leukaemia Laboratory, Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Chung
authors.initials: C
authors.lastname: Kok
authors.affiliation: Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Luen B
authors.initials: LB
authors.lastname: To
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, Australia; Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia. Electronic address: andrew.zannettino@adelaide.edu.au.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D023061:Gene Order; D016147:Genes, Tumor Suppressor; D056426:Genetic Loci; D006801:Humans; D008297:Male; D051379:Mice; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C435526:SAMSN1 protein, human; C000596182:SLy2 protein, mouse