published_or_final_version / abstract / Biochemistry / Master / Master of Philosophy

Murine plasmacytoma is induced by plastic implants, injection of paraffin oil or pristane, or through viral infection, and Myc is invariably overexpressed in the tumour cells. Although translocation and juxtaposition of the Myc locus to an immunoglobulin locus is the prominent nonrandom cytogenetic aberration observed, the significance of other karyotypic instabilities in murine plasmacytoma is not clear, including the previously observed occurrence of trisomy 11. As well as identifying new cytogenetic mutations in murine plasmacytomagenesis, this study provides evidence for their combined and sequential accumulation that may offer new parallels to human B-cell malignancies. Plasmacytomas were induced in Balb/c Rb6.15 mice by intraperitoneal (i.p.) pristane injection prior to infection with the ABL-MYC retrovirus, and confirmed by histological examination. Spectral karyotype analysis of tumour samples identified frequent aneuploidy, tetraploidy, and amplification of chromosomes 11, 12 and 16. In contrast, control mice treated by i.p. pristane injection did not develop plasmacytoma, and lipopolysaccharide-stimulated splenocytes from control mice had mainly normal diploid karyotypes. However, karyotypic instability in a minority of splenocytes indicated that control mice showing no signs of plasmacytoma development nevertheless are prone to numerical and structural cytogenetic mutations that may possibly result in plasmacytoma initiation and progression under favourable conditions, such as infection with ABL-MYC virus with the resulting high expression of v-abl and Myc in target cells. These results indicate the possible existence of proto-oncogenes present on murine chromosomes 11, 12, and 16 that are important for plasmacytoma initiation and/or progression. There are also indications that T(1;6) and monosomy of the X chromosome may also play roles in plasmacytomagenesis, and that trisomy 12 may only occur in cells with pre-existing nonrandom mutations, thereby acting as a late mutation event. As other experimental models of murine plasmacytoma have not shown a similar karyotypic etiology, there appears to be several possible redundant cytogenetic mutation events that lead to plasmacytoma. Also, as tumours in this study present various combinations of the aforementioned amplified chromosomes, their combined amplification may serve redundant purposes as well. / May 2008

Murine plasmacytoma is induced by plastic implants, injection of paraffin oil or pristane, or through viral infection, and Myc is invariably overexpressed in the tumour cells. Although translocation and juxtaposition of the Myc locus to an immunoglobulin locus is the prominent nonrandom cytogenetic aberration observed, the significance of other karyotypic instabilities in murine plasmacytoma is not clear, including the previously observed occurrence of trisomy 11. As well as identifying new cytogenetic mutations in murine plasmacytomagenesis, this study provides evidence for their combined and sequential accumulation that may offer new parallels to human B-cell malignancies. Plasmacytomas were induced in Balb/c Rb6.15 mice by intraperitoneal (i.p.) pristane injection prior to infection with the ABL-MYC retrovirus, and confirmed by histological examination. Spectral karyotype analysis of tumour samples identified frequent aneuploidy, tetraploidy, and amplification of chromosomes 11, 12 and 16. In contrast, control mice treated by i.p. pristane injection did not develop plasmacytoma, and lipopolysaccharide-stimulated splenocytes from control mice had mainly normal diploid karyotypes. However, karyotypic instability in a minority of splenocytes indicated that control mice showing no signs of plasmacytoma development nevertheless are prone to numerical and structural cytogenetic mutations that may possibly result in plasmacytoma initiation and progression under favourable conditions, such as infection with ABL-MYC virus with the resulting high expression of v-abl and Myc in target cells. These results indicate the possible existence of proto-oncogenes present on murine chromosomes 11, 12, and 16 that are important for plasmacytoma initiation and/or progression. There are also indications that T(1;6) and monosomy of the X chromosome may also play roles in plasmacytomagenesis, and that trisomy 12 may only occur in cells with pre-existing nonrandom mutations, thereby acting as a late mutation event. As other experimental models of murine plasmacytoma have not shown a similar karyotypic etiology, there appears to be several possible redundant cytogenetic mutation events that lead to plasmacytoma. Also, as tumours in this study present various combinations of the aforementioned amplified chromosomes, their combined amplification may serve redundant purposes as well.

Murine plasmacytoma is induced by plastic implants, injection of paraffin oil or pristane, or through viral infection, and Myc is invariably overexpressed in the tumour cells. Although translocation and juxtaposition of the Myc locus to an immunoglobulin locus is the prominent nonrandom cytogenetic aberration observed, the significance of other karyotypic instabilities in murine plasmacytoma is not clear, including the previously observed occurrence of trisomy 11. As well as identifying new cytogenetic mutations in murine plasmacytomagenesis, this study provides evidence for their combined and sequential accumulation that may offer new parallels to human B-cell malignancies. Plasmacytomas were induced in Balb/c Rb6.15 mice by intraperitoneal (i.p.) pristane injection prior to infection with the ABL-MYC retrovirus, and confirmed by histological examination. Spectral karyotype analysis of tumour samples identified frequent aneuploidy, tetraploidy, and amplification of chromosomes 11, 12 and 16. In contrast, control mice treated by i.p. pristane injection did not develop plasmacytoma, and lipopolysaccharide-stimulated splenocytes from control mice had mainly normal diploid karyotypes. However, karyotypic instability in a minority of splenocytes indicated that control mice showing no signs of plasmacytoma development nevertheless are prone to numerical and structural cytogenetic mutations that may possibly result in plasmacytoma initiation and progression under favourable conditions, such as infection with ABL-MYC virus with the resulting high expression of v-abl and Myc in target cells. These results indicate the possible existence of proto-oncogenes present on murine chromosomes 11, 12, and 16 that are important for plasmacytoma initiation and/or progression. There are also indications that T(1;6) and monosomy of the X chromosome may also play roles in plasmacytomagenesis, and that trisomy 12 may only occur in cells with pre-existing nonrandom mutations, thereby acting as a late mutation event. As other experimental models of murine plasmacytoma have not shown a similar karyotypic etiology, there appears to be several possible redundant cytogenetic mutation events that lead to plasmacytoma. Also, as tumours in this study present various combinations of the aforementioned amplified chromosomes, their combined amplification may serve redundant purposes as well.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available online.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Murine plasmacytoma models human cancers that involve deregulation of MYC. Overexpression and duplication of the immature colon carcinoma transcript 1 gene, Ict1, along with MYC deregulation may contribute to the aggressive mechanism for disease development in fast-onset mouse plasmacytomas. This study looks at Ict1 and c-MYC overexpression in mouse PreBmycER cells that serve as a cell culture model for MYC-dependent plasmacytomagenesis. An Ict1 inducible vector was transfected into the mouse PreBmycER cell line that contains inducible c-MYC. This allowed us to examine the effect of overexpression of ICT1 and c-MYC proteins simultaneously or each separately, on selected hallmark cancer cell traits such as increased proliferation, evasion of apoptosis and increased genomic instability. An increase in the number of cells in the S-phase was observed by 15 % and up to 20 % at 24 and 36 hours respectively, and cell doubling time shortened by almost 2 hours at 24 hours during peak ICT1 and c-MYC overexpression. Although, no noticeable change in apoptosis levels, or large scale genomic alterations were detected up to 96 hours post-ICT1 and c-MYC peak-overexpression, genomic instability was observed when MYC protein was overexpressed with or without ICT1 protein overexpression. Extrachromosomal elements increased in number and size during conditional MYC deregulation, and most of these elements (25 %) classified as Chromosome 11. These findings support Ict1 as a candidate gene that is selected for by MYC-deregulation during plasmacytomagenesis, and show promise that the experimental model of induced MYC and ICT1 overexpression in mouse PreB cells, deserves further investigation, specifically with in vivo studies. / October 2016

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [85]-98).

The basic helix-loop-helix protein, activated B-cell factor-l (ABF-l), is a transcription factor involved in cellular proliferation and differentiation. ABF-1 shows patterns of expression that are stimulated in activated B cells, which may suggest ABF-1 is involved in the regulation of B-cell differentiation. To investigate the functional role of ABF-1, we have generated a human plasmacytoma cell line with inducible expression of ABF-1. We were able to induce expression of ABF-1 by using the tetracycline repressor system (teton/off). With addition of tetracycline we were able to stimulate the expression of the full-length ABF-1 in the cells. We also got induction of the truncated form of ABF-1, lacking the protein dimerization domain (HLH), with the addition of tetracycline. We then compared these two cell lines to uninduced cells. We confirmed that ABF-1 expression was induced by western blot analysis. We conclude that we have developed a human plasmacytoma cell line with inducible expression of ABF-1 and can use this cell line for further studies.

Solitary extramedullary plasmacytomas are uncommon neoplasms. They occur most frequently in the upper aerodigestive tract and account for 4% of the nonepithelial tumors in this site. The evolution of a plasmacytoma is unsteady and symptoms at presentation have included dystonia, dysphagia, oral pain, cough, and dyspnea on exertion. Plasmaeytoma of the upper aerodigestive tract has not been previously reported as a cause of obstructive sleep apnea.