Immunohistochemical analysis of cyclin D1 shows deregulated expression in multiple myeloma with the t(11;14)

Abstract

The t(11;14)(q13;q32) chromosomal translocation, the hallmark of mantle cell lymphoma (MCL), is recurrently found in multiple myelomas (MM) by means of conventional cytogenetics. Unlike MCL, recent molecular studies of MM-derived cell lines with t(11;14) have indicated that the breakpoints are highly dispersed over the 11q13 region; however, the fact that cyclin D1 is generally overexpressed in these cell lines suggests that this gene is the target of the translocation. To evaluate further the involvement of cyclin D1 in MM, we used immunohistochemistry and fluorescence in situ hybridization to investigate cyclin D1 expression and the presence of chromosome 11 abnormalities in a representative panel of 48 MM patients (40 at diagnosis and 8 at relapse). Cyclin D1 overexpression occurred in 12/48 (25%) of cases; combined immunohistochemistry and fluorescence in situ hybridization analyses in 39 patients showed cyclin D1 positivity in all of the cases (7/7) bearing the t(11;14), in two of the 13 cases with trisomy 11, and in one of the 19 cases with no apparent abnormalities of chromosome 11. Our data indicate that the t(11;14) translocation in MM leads to cyclin D1 overexpression and that immunohistochemical analysis may represent a reliable means of identifying this lesion in MM.

Figure 1.

IHC analysis of MMs. A: Positive control (diffusely infiltrated bone marrow biopsy by a MCL case). B: A representative case (no. 35) of a cyclin D1-negative MM showing only a very few scattered positive plasma cells (below the 10% threshold; see text) in the biopsy specimen. C−E: Neoplastic plasma cell nuclei from positive cases (nos. 8, 26, and 39, respectively). Hematoxylin counterstain; original magnification, ×630.

Figure 2.

FISH analysis of 11q13 breakpoints in MM. Red signal: YAC 744; green signal: FGF3; dissociated signals specific for FGF3 (green) are indicated by arrows; the signal (green) from the α-satellite DNA probe specific for chromosome 11 is indicated by arrowhead. A and B: Interphase and metaphase nuclei from a normal control. C and D: Interphase and metaphase nuclei with an 11q13 breakpoint in case no. 26. E and F: Interphase and metaphase nuclei with an 11q13 breakpoint in case no. 34; two dissociated green signals are found due to a duplication of the putative derivative chromosome. G and H: Interphase and metaphase nuclei with an 11q13 breakpoint in case no. 39. I and J: Interphase and metaphase nuclei with an 11q13 breakpoint in case no. 47; there was evidence that the breakpoint is within YAC 744 as the signal was split and associated with the FGF3 in a derivative chromosome. K and L: Interphase and metaphase nuclei of case no. 23 with trisomy 11.

Figure 3.

FISH analysis of the t(11;14) translocation in MM with 11q13 breakpoints. A and B: Interphase and metaphase FISH in case no. 39. C: Interphase FISH in case no. 34. D: Metaphase FISH in case no. 47. Red signal (FGF3); green signal (IGH-constant μ, γ1–4, α1–2 regions). The arrows indicate the FGF3-IGH association on the putative 14 (der).