Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to lasercapture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage IntroductionClassical Hodgkin lymphoma (cHL) is a B-cell malignancy that occurs frequently in Western countries and commonly affects young adults. 1 These tumors are characterized by small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive inflammatory/immune cell infiltrate. There are 4 subtypes of cHL, 2 of which comprise Ϸ 90% of cases: nodular sclerosing Hodgkin lymphoma (NSHL; 60% of cases) and mixed cellularity Hodgkin lymphoma (MCHL; 30% of cases). cHLs lack surface immunoglobulin expression and B-cell receptor-mediated signals and rely on alternative survival pathways, including aberrant nuclear factorB signaling. 1 In previous studies, we and others have defined shared molecular features of cHL and a specific subtype of diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (MLBCL). 2,3 Like cHL, MLBCLs have a T-helper cell type 2 (Th2)-skewed cytokine profile, decreased expression of B-cell receptor signaling pathway components, and constitutive activation of nuclear factorB. 2 MLBCL also exhibits certain clinical and histologic similarities to cHL, particularly the NSHL subtype. 4,5 For example, both diseases are most common in young adults and often present as an anterior mediastinal or localized nodal mass. 2,4,5 In addition, both MLBCLs and NSHLs include bands of sclerotic tissue and immune/inflammatory cell infiltrates. 4,5 However, the inflammatory infiltrate is less prominent in MLBCLs, which have a more diffuse growth pattern. 4 Although cHLs have an extensive polymorphous inflammatory infiltrate, there is little evidence of an effective host antitumor immune response. In fact, recent studies indicate that Hodgkin RS cells pro...

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…Patients with the 9p24.1 gain/amplification did not reveal particular clinical features, but their mean survival was slightly shorter than in the remaining EBV Copy number gain of 9p24.1 is a known aberration in lymphoma, particularly in primary mediastinal B cell lymphoma (PMBCL) and classic Hodgkin lymphoma (cHL) (14)(15)(16)(17). It was postulated that in PMBCL this aberration leads to increased dosage of both PDL1 and PDL2, and their induction by the neighboring JAK2 (14). PDL1/2 signal through the programmed death receptor PD-1 and deliver co-inhibitory signals that regulate T cell activation, T cell tolerance, and immune defenses against microbial pathogens (18).…”

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