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Review
. 2021 Feb 8;13(4):682.
doi: 10.3390/cancers13040682.

Genomic Landscape of Hodgkin Lymphoma

Magdalena M Brune  1 , Darius Juskevicius  1 , Jasmin Haslbauer  1 , Stefan Dirnhofer  1 , Alexandar Tzankov  1
Affiliations
Review

Genomic Landscape of Hodgkin Lymphoma

Magdalena M Brune et al. Cancers (Basel). .

Abstract

Background: Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded the analysis of the tumor cell genomes for a long time, but recently developed methods (especially laser capture microdissection, flow cytometry/fluorescence-activated cell sorting) facilitated molecular investigation, elucidating the pathophysiological principles of "Hodgkin lymphomagenesis".

Methods: We reviewed the relevant literature of the last three decades focusing on the genomic landscape of classic and nodular lymphocyte predominant HL (NLPHL) and summarized molecular cornerstones.

Results: Firstly, the malignant cells of HL evade the immune system by altered expression of PDL1/2, B2M and MHC class I and II due to various genetic alterations. Secondly, tumor growth is promoted by permanently activated JAK/STAT signaling due to pervasive mutations of multiple genes involved in the pathway. Thirdly, apoptosis of neoplastic cells is prevented by alterations of NF-κB compounds and the PI3K/AKT/mTOR axis. Additionally, Epstein-Barr virus infection can simultaneously activate JAK/STAT and NF-κB, similarly leading to enhanced survival and evasion of apoptosis. Finally, epigenetic phenomena such as promoter hypermethylation lead to the downregulation of B-lineage-specific, tumor-suppressor and immune regulation genes.

Conclusion: The blueprint of HL genomics has been laid, paving the way for future investigations into its complex pathophysiology.

Keywords: 9p24 locus; Epstein-Barr virus; Hodgkin lymphoma; JAK/STAT; NF-κB; PDL1; PDL2; PI3K/AKT/mTOR; cell enrichment; cell lines; epigenetics; genomes; mutations.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of known genetic aberrations in classic Hodgkin lymphoma (cHL) arranged according to aberration type and color-coded according to the affected cellular process that they dysregulate in Hodgkin and Reed-Sternberg cells; genes encoding for proteins related to apoptosis are in red, to B-cell identity—in brown, to cytokine (mainly JAK-STAT) signaling—in orange, to NF-κB signaling—in green, to immune escape—in blue, and to cytokinesis, chromatin/DNA/RNA functions—in black; inactivating translocations of SOCS1 that are characteristic of pediatric cHL [13] are not sown.
Figure 2
Figure 2
(A) PDL1 overexpressing Hodgkin and Reed-Sternberg (HRS) cells in a case of PDL1/2 amplified classic Hodgkin lymphoma (cHL). (B) HRS cells expressing phosphorylated (p) JAK2 in a JAK2 rearranged cHL (insert with split red and green FISH signals corresponding to the rearranged allele and one fused yellow signal corresponding to the wild type allele of the JAK2 gene in the respective large HRS cell-equivalents utilizing a break-apart JAK2 probe). (C) pSTAT6 overexpressing HRS cells in a case of STAT6-mutated cHL. (D) Expression of pSTAT6 only in a few HRS cells as compared to. (E) pSTAT5 and, particularly, pSTAT3. (F) in a case of SOCS1-mutated cHL.
Figure 3
Figure 3
(A) BOB1-negative Reed-Sternberg (RS) cell surrounded by BOB1 positive B-cells; BOB1 inactivation due to promoter hypermethylation of the respective gene in classic Hodgkin lymphoma (cHL). (B) SMAD1 negative RS cells surrounded by SMAD1 positive lymphocytes; SMAD1 is known to be hypermethylated in cHL and nodular lymphocyte-predominant Hodgkin lymphoma.
See this image and copyright information in PMC

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