Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma

Abstract

The pathogenesis of multiple myeloma (MM), an incurable tumour causing the deregulated proliferation of terminally differentiated B cells, is unknown. Chromosomal translocations (14q1) affecting band 14q32 and unidentified partner chromosomes are common in this tumour, suggesting that they may cause the activation of novel oncogenes. By cloning the chromosomal breakpoints in an MM cell line, we show that the 14q+ translocation represents a t(6;14)x(p25;q32) and that this aberration is recurrent in MM, as it was found in two of eleven MM cell lines. The translocation juxtaposes the immunoglobulin heavy-chain (IgH) locus to MUM1 (multiple myeloma oncogene 1)/IRF4 gene, a member of the interferon regulatory factor (IRF) family known to be active in the control of B-cell proliferation and differentiation. As a result, the MUM1/IRF4 gene is overexpressed--an event that may contribute to tumorigenesis, a MUM1/IRF4 has oncogenic activity in vitro. These findings identify a novel genetic alteration associated with MM, with implications for the pathogenesis and diagnostics of this tumour.

Somatic stem cells and the origin of cancer

“…Notably, many of the genes involved in the lymphocyte developmental network are targeted in such chromosomal translocations, namely PAX5, OBF1, BCL11A, BCL6, IRF4/MUM1, Ikaros, NOTCH1 and FOXP1 (table 1) 155,164,183,[185][186][187][188][189][190][191] . Other regulatory genes are also altered through alternative genetic mechanisms, such as gene amplification of the NF-κB family gene REL, activating mutation of NOTCH1 and inactivating mutation of BLIMP1 119,[192][193][194] .…”

Chromosome translocations in multiple myeloma

“…A t(6;14) (p25;q32) translocation breakpoint was cloned from a MM cell line and found to occur immediately downstream of the IRF-4 gene, a member of the interferon regulatory factor family active in the control of B cell proliferation and di erentiation (Iida et al, 1997). This translocation was identi®ed by metaphase FISH analyses in three of 17 (18%) MM cell lines that were screened (Yoshida et al, 1999).…”

“…Through a combination of strategies, we and others have cloned 40 IgH translocation breakpoints (but no IgL translocation breakpoints) in MM cell lines and tumors Chesi et al, 1996Chesi et al, , 1997Chesi et al, , 1998aGabrea et al, 1999;Hatzivassiliou et al, 2001;Iida et al, 1997;Pratt et al, 2001;Richelda et al, 1997;Ronchetti et al, 1999;Shaughnessy et al, 2001;Bergsagel and Kuehl, 2001, unpublished). With the exception of a few translocation breakpoints within the JH region, most of these breakpoints were identi®ed using probes designed to detect ISRF, so that the results are signi®cantly biased in identifying translocations that occur within or relatively near an IgH switch region.…”

MUM1: a step ahead toward the understanding of lymphoma histogenesis

“…MUM1 originally gained attention from molecular hematologists because of its involvement in the t(6;14)(p25;q32) translocation of multiple myeloma, which causes the juxtaposition of the MUM1 gene, mapping at 6p25, to the Ig H locus on 14q32. 16,17 Before being discovered as a protooncogene of hematologic neoplasia, though, MUM1 had been extensively investigated by immunologists who defined that MUM1 is a lymphocyte-specific member of the interferon regulatory factor family of transcription factors. 18 Hence, the various names assigned to MUM1, which include IRF4 (for Interferon Regulatory Factor 4), ICSAT (for Interferon Consensus Sequence binding protein for Activated T cells) and Pip (for PU.1 Interaction Partner).…”