The molecular pathogenesis of primary mediastinal large B-cell lymphoma

Abstract

Primary mediastinal large B-cell lymphoma (PMBCL) is a recognized nonHodgkin lymphoma entity with unique pathologic, clinical, and molecular characteristics distinct from those of other diffuse large B-cell lymphomas. Immunohistochemical characterization and molecular studies strongly suggest that PMBCL is of germinal center or postgerminal center origin. Pivotal gene expression profiling work defined major deregulated pathway activities that overlap with Hodgkin lymphoma and prompted a more detailed analysis of candidate genes. In particular, the nuclear factor-B and the Janus Kinase-Signal Transducer and Activator of Transcription signaling pathways are targeted by multiple genomic hits, and constitutive activity of both pathways can be considered molecular hallmark alterations of PMBCL. Moreover, data are emerging giving unique insight into remodeling of the epigenome that affects transcriptional regulation of a multitude of genes. More recently, the tumor microenvironment of PMBCL has shifted into focus based on a number of gene perturbations altering expression of surface molecules that contribute to immune escape. These findings highlight the importance of immune privilege in the pathogenesis of PMBCL and suggest that disrupting crosstalk between the tumor cells and the microenvironment might be a rational new therapeutic target in conjunction with traditional treatment strategies.

Targetable genetic features of primary testicular and primary central nervous system lymphomas

“…14 PMBL is a distinct LBCL subtype that exhibits constitutive NF-kB activation and shares certain clinical and genetic features with classical Hodgkin lymphoma (cHL). 15 We and others identified 9p24.1/CD274 (PD-L1)/PDCD1LG2(PD-L2), copy gain, and increased expression of the PD-1 ligands in 65% of PMBLs. 16,17 Translocations of PD-L1 and PD-L2 were also reported in PMBL.…”

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

“…Next-generation sequencing (NGS) technologies, enabling high-throughput DNA sequencing, have emerged over the past decade and have provided new insights into the genomic characterization of DLBCL by identifying recurrent single nucleotide variants (SNV), which can be enriched in a particular subtype (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Although DLBCL is defined by widespread genetic heterogeneity, several of the pinpointed recurrent SNVs warrant special interest as they occur in actionable targets and/or correlate with antitumoral response.…”

Cytogenetics and molecular cytogenetics in diffuse large B-cell lymphoma (DLBCL)

“…Patients diagnosed with PMBL typically have gains of the long arms of chromosome 9, in particular of the 9p24 region. This cytogenetic aberration has become a characteristic feature of PMBL patients 23 . Duplication or multiplication of this locus is associated with upregulation of the Janus kinase 2 (JAK2) gene.…”

“…Most frequently, cytogenetic changes involving REL, PDL1/ PDL2, JAK2, JMJD2C and CIITA were reported 23 . Patients diagnosed with PMBL typically have gains of the long arms of chromosome 9, in particular of the 9p24 region.…”

“…These chromosome regions contain IGF1, ELK3, EPS8 and IFNG, candidate genes associated with malignant transformation 24 . Recent studies have been searching for the role of these genes in DLBCL lymphomagenesis 23 . So far, genetic studies of DLBCL have confirmed the diagnostic and prognostic impact of recurrent chromosomal aberrations mainly serving as markers for stratification into prognostic subgroups.…”