CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1^- MCL has been recognized, and approximately one-half of them harbor <i>CCND2</i> translocations while the primary event in cyclin D1^-/D2^- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1^-/SOX11⁺ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified <i>CCND2</i> rearrangements in 39 cases (70%) but not <i>CCND3</i> rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near <i>CCND3</i> that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to <i>CCND3</i> (6 cases) and <i>CCND2</i> (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1^- MCL cases lacked cyclin D rearrangements and showed upregulation of <i>CCNE1</i> and <i>CCNE2.</i> These cases had blastoid morphology, high genomic complexity, and <i>CDKN2A</i> and <i>RB1</i> deletions. Both genomic and gene-expression profiles of cyclin D1^- MCL cases were indistinguishable from cyclin D1⁺ MCL. In conclusion, virtually all cyclin D1^- MCLs carry <i>CCND2/CCND3</i> rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1^-/D2^-/D3^- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1^- MCL.