摘要：

Purpose:Recurrent chromosomal translocations are regularly involved in hematological malignancies and may up-regulate existing (proto)oncogenes or create new hybrid genes with transforming properties. Multiple myeloma (MM) is an intractable neoplastic disease of plasma cells in the bone marrow. Karyotyping has detected a wide range of abnormalities with rearrangements involving 14q32 as a common theme. Also via molecular techniques 14q32 translocations with a variety of translocation partners have been reported recently.In fluorescent in situ hybridization (FISH) studies we detected the involvement of the Immunoglobulin Heavy chain (IgH) locus in these 14q32 translocations in virtually all MM cell lines tested, with a diverse array of translocation partners. This is a higher frequency of IgH translocations than reported so far by other techniques, and demonstrates the high sensitivity of FISH for resolving defined translocations. Others and we detected these 14q32 translocations especially in the switch regions, which fits with the putative post-follicular dedifferentiation of MM. It suggests that IgH translocations may be crucial for the development of MM and that various oncogenes are involved in the etiology of MM. Recent molecular studies have recognized four major 14q32 translocations, i.e. involving 4p16, 6p25, 11q13 and 16q23; the putative oncogenes of these recurrent translocations are being described. We have cloned the breakpoint and are defining the putative oncogene(s) involved in yet another recurrent translocation, i.e. the t(14;20)(q32;q11). We aim to study:- the elucidation of the gene(s) involved in t(14;20)(q32;q11)- the status of this 14q32 translocation in staging, prognosis and grouping of MM.Plan of investigation:We will focus on the recurrent t(14;20)(q32;q11); the scatter in these breakpoints and the deregulated gene(s) are unknown as yet. The oncogenicity of candidate oncogene(s) will be tested by transgenesis. The contribution of this translocation to the ontogeny of MM will be traced by examining the interphase distribution of probe pairs, which characterize specific breakpoints in bone marrow samples at various intervals during the disease. We maintain a large library of such samples collected over the years and (also by having set up reliable methods to combine two FISH probes with Ig staining) we are able to perform such studies retrospectively, to discriminate between early and late oncogenic events.Possible results and relevance for cancer research:Our studies on the recurrent 20q11 translocation locus will complement existing molecular studies on other translocations in MM. Our studies are included in a Dutch program on clinicopathological aspects of MM. The identification of genes, associated with IgH enhancers will add to the elucidation of molecular processes, underlying the malignant transformation leading to MM; it may further permit characterization of clinically different subgroups and open new alleys in specific (e.g. IgH enhancer directed) pharmacotherapeutical approaches to B cell malignancies.

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