Statistics
Every year approximately 1,300 Canadian die of multiple myeloma (MM), an incurable B cell neoplasia characterized by the dysregulated clonal expansion of malignant plasma cells. The prognosis for patients with MM is steadily improving over the years and great strides have been made in understanding the biology of this disease. The average survival for myeloma is now 5-6 years from time of diagnosis. Although incurable, up to 20% of patients may live over 10 years. The current treatment regimen is autologous stem cell transplant in combination with high dose chemotherapy.

The cause of the neoplastic transformation in multiple myeloma is linked with genetic events preceeded by illegitimate IgH switch recombinations resulting in chromosomal translocations, followed additional karyotypic instability that occur throughout the progression of the tumour. In a significant fraction of reported cases, activation of oncogenes by translocation events are common causes, but there are reports that some multiple myeloma cases have familial component. The nature of the predisposing genetic lesions in familial cases is unknown. A better genetic and molecular understanding of the genesis of plasma cell would provide better treatment regimen and offers development of alternative therapies.

Dysregulated oncogenes in multiple myeloma
The development of myeloma constitutes progressive genetic events. The seminal event in the pathogenesis of myeloma is the translocation of oncogenes to the IgH locus on 14q32. At least six genes have been identifed as 14q32 translocation partners: c-myc, Bcl-1/PRAD-1/cyclin D1, FGFR3, MUM1/IRF4, cyclin D3 and c-maf. As the disease progresses, depending on the clinical nature of the myeloma, mutations in genes such as N-ras, K-ras and p53 may occur.

(1) c-myc. (8q24) Translocations involving t(8;14) occurs in less than 5% of human multiple myeloma cases, but between 10 to 20% of tumors have genetic abnormalities near this locus (Bergsagel, 1998). The exact pathogenic mechanism resulting from the dysregulation of c-myc, the cellular homologue of the avian retrovirus v-myc gene, has not been fully understood. Except for the upregulation at the mRNA or protein levels in some studies (Selvanayagam, 1988; Paulin, et al 1996), the molecular pathway leading to the development of tumour as a result of the deregulation of c-myc remains unknown.

(2) Bcl-1/PRAD-1/cyclin D1 (11q13) A cluster of translocation events occur in this locus resulting in chronic lymphocytic leukemia (CLL) and lymphoma. Although studies of translocations in this region have identified cyclin D1 as the affected gene (Seto et al., Komatsu et al), there are is yet no extensive studies that define the extent of its contribution to the pathogenesis of myeloma.

(3) FGFR3 and/or MMSET (4p16.3) Approximately 25% of myeloma has translocation of the receptor tyrosine kinase FGFR3 to the IgH locus. It is believed that an activating somatic mutation occurs after the translocation event resulting in constitutive activation of the receptor in the absence of ligand. Interestingly, germline mutation in FGFR3 also results in drawfism (chondrodysplasia) and premature fusion of skull bones (craniosynostosis) seen in thanatophoric dysplasia. (Tavormina et al. 1995) Naski et al., 1996).

(4) MUM1/IRF4/ICSAT/PIP/LSIRF (6p25) IRF4 is a member of the interferon regulatory factor family which are know to be involved in B-cell proliferation and differentiation. Translocation of MUM1/IRF4 into the IgH locus appears to keep the entire transcription unit intact suggesting that IgH regulatory elements takeover the control of MUM1/IRF4 expression leading. This recurrent translocation was seen in 2 of 11 MM.

(5) Cyclin D3 (6p21) is overexpressed in ~3% of multiple myeloma cell lines and ~4% of primary multiple myeloma tumors.

(6) c-maf (16q23) c-maf is a proto-oncogene that is a member of a large family of basic transcription factor that include jun and fos. Translocation of c-maf into the IgH locus results in overexpression of c-maf in approximately 25% of mutiple myeloma cell lines. Like the translocations involving Mum1, c-myc, bcl-2 and cyclin D1, oncogenic transformation of plasma cells by translocation of c-maf alters its expression level while retaining the normal coding region of the gene.

In all the recurrent translocations mentioned above, the molecular pathogenic mechanism is the dysregulation of the affected gene by overexpression at the RNA level. In the case of Mum1 and cyclin D1, such dysregulation also results in the apparent overexpression of the gene at the protein level.