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Characterization of 14q32 Translocations In Multiple Myeloma
By P. Leif Bergsagel
10.01.97
Cancer is proposed to result from the progressive accumulation of genetic events in a cell susceptible to malignant transformation. In lymphocytic tumors, the most prominent such event is a chromosome translocation, frequently involving the antigen receptor genes, presumably related to the normal DNA rearrangements that occur at these loci. Deregulated expression of oncogenes by translocation into the immunoglobulin heavy chain (IgH) locus at 14q32 is a critical event in many B cell malignancies. The identification of these genes (c-myc, bcl-2, cyclin D1) has had a profound influence on our understanding of cell cycling, proliferation, differentiation and death, that extends far beyond their role in B cell tumors.

Based on this model of tumor progression, the goal of the proposed research is to characterize the genetic events associated with the development and progression of plasma cell neoplasms. We will begin with a careful analysis of translocations to the IgH locus in these conditions. The molecular pathogenesis of multiple myeloma (MM) is poorly understood, and no consensus genetic changes have been identified, although a 14q+ is the most frequent karyotypic abnormality. Because MM cells are mature, isotype switched plasma cells, we have hypothesized that these 14q+ may represent from an illegitimate switch recombination, a marker of a translocation into a switch region. We detected frequent illegitimate switch recombination fragments in MM cell lines, and have cloned these from 8 cell lines, and 1 patient. In each case we identified a 14q32 translocation breakpoint: 4p16 in three, 11q13 in three and 6, 8, 16q23, 21 once each. We hypothesize that as in other B cell tumors, these translocations are important in the pathogenesis of plasma cell neoplasms, presumably through deregulated expression of a critical gene on the partner chromosome. They may have a role in initiating the malignancy, or in its progression.

Identifying these genes and determining the role they play in the development and progression of plasma cell neoplasms will provide a framework to understand the pathogenesis of these tumors, and allow the development of rational treatment and prevention strategies. As in mantle cell lymphoma, the t(11;14) in myeloma are associated with the over-expression of cyclin D1. The t(4;14)(p16;q32) has not been described before, and may be unique to myeloma. The 4p16 breakpoints are located 20-60 kb centromeric to fibroblast growth factor receptor 3 (FGFR3) and are associated with the ectopic expression of FGFR3. We have not yet looked for any genes expressed as a result of the other translocations. Based on these observations, we now propose to examine primary samples from patients with MM to:

Aim 1. Identify partner chromosomes involved in IgH translocations in malignant plasma cells;

Aim 2. Identify specific genes subject to abnormal regulation by translocation;

Aim 3. Study the role of the dysregulated genes in the pathogenesis of plasma cell neoplasms.

The identification of the ectopic expression of FGFR3 in MM is particularly exciting. If it is shown to be a functional receptor, there are numerous options for specifically targeting it and interfering with its signaling. We can expect such directed strategies to have minimal toxicity, as FGFR3 is not widely expressed and only appears to be important in chondrocyte development. Thus, these basic studies in the molecular pathogenesis of MM hold promise for the rapid translation to clinically relevant treatment strategies.

Cancer is proposed to result from the progressive accumulation of genetic events in a cell susceptible to malignant transformation. In lymphocytic tumors, the most prominent such event is a chromosome translocation, frequently involving the antigen receptor genes, presumably related to the normal DNA rearrangements that occur at these loci. Deregulated expression of oncogenes by translocation into the immunoglobulin heavy chain (IgH) locus at 14q32 is a critical event in many B cell malignancies. The identification of these genes (c-myc, bcl-2, cyclin D1) has had a profound influence on our understanding of cell cycling, proliferation, differentiation and death, that extends far beyond their role in B cell tumors.
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