Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines

Abstract

Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2–10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets.

STAT6 is a cargo of exportin 1: Biological relevance in primary mediastinal B-cell lymphoma

“…indicates a constitutive activated JAK2/STAT6 signalling pathway [21]. This can be the consequence of an amplification of the JAK2 gene [22], recurrent mutations of SOCS1 or PTPN1 genes [23][24][25]. In agreement with previous studies, we observed that p-Tyr641-STAT6…”

Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

“…In diffuse large B-cell lymphoma (DLBCL) high COMMD1 expression is correlated with poor prognosis [2] and is associated with aggressive forms of (DLBCL) [42]. Increased COMMD1 expression is also common in primary mediastinal B-cell lymphoma (PMBL) cells lines and in PMBL patients [43]. In contrast, in many other types of cancer (e.g.…”

Biology and therapy of primary mediastinal B‐cell lymphoma: current status and future directions

“…In vitro, neutralizing antibodies directed against CD2 or CD58 prevents conjugate formation and decreases T‐cell activity (Mak & Saunders, ). The CD58 locus in PMBCL was found to be targeted by mono‐ and bi‐allelic microdeletions in 3 of 4 cell lines and in 5 primary tissues interrogated, resulting in conspicuous silencing of CD58 gene expression (Dai et al , ). Although functional studies in PMBCL are lacking, reconstitution of CD58 in a null DLBCL cell line increased NK‐cell mediated cytolysis (Challa‐Malladi et al , ).…”