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Page 139 Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46

the interpretation of the studies. Consequently, the literature is inconclusive with respect to potential
difference in effect of frontline therapy (including ABVD and escBEACOPP) between EBV-positive and
EBV-negative cHL.

EBV rescues pre-apoptotic germinal center cells
The scarcity of HRS cells in cHL tumour lesions for long hindered establishment of their cellular origin.
However, in addition to being positive for the lymphocyte activation antigen CD30, genetic analyses
revealed that most HRS cells carry clonal immunoglobulin chain gene rearrangements but are incapable of
expressing immunoglobulins, implying that they are derived from pre-apoptotic germinal center B
cells [49-51] . Despite their B-cell derivation the HRS cells do not express B-cell receptors which also would
[52]
normally lead to their demise .
Though destined to undergo apoptosis, their continued survival and transformation into HRS cells implies
that the cells at some point were rescued from the programmed apoptosis, which may be accomplished by
EBV [53,54] .

In EBV-positive HRS cells, EBV establishes a latency II program characterized by the expression of the viral
proteins EBNA1, LMP1 and LMP2A and -2B along with EBERs and BART miRNA transcripts [53,55] . These
viral gene products, most importantly LMP1, LMP2A and EBNA1, may substitute the cellular deficits to
circumvent the pre-programmed apoptosis and to model the TME. LMP1 for instance mimics an activated
CD40 receptor and stimulates the NF-κB, PI3-Akt and JAK/STAT pathway activity characteristic of HRS
cells [55,56] . Moreover, in primary germinal center B-cells LMP1 has been shown to be capable of
downregulating B-cell transcription factors and B-cell receptor signalling components and upregulate
survival genes such as BCL2 and BFL-1 [55,56] . LMP2A mimics the functions of an activated B-cell receptor
[56]
and engages the RAS/PI3/AKT pathways critical of HRS cell survival . LMP2A also suppresses the
expression of transcription factors such as EBF1 and E2A and activates the Notch pathway [55,56] . EBNA1 in
addition to sustaining viral and cellular gene expression and correct viral replication also contribute to HRS
cell growth and survival through downregulation of the protein tyrosine phosphatase receptor type K
(PTRPK) .
[55]

Lacking the virus but sharing fatal cellular characteristics with EBV-positive HRS cells, mechanisms that
exert effects corresponding to those of EBV necessarily must exist to account for EBV-negative HRS cells.
Although it has been speculated that EBV-negative HRS cells might initially have been EBV infected but lost
[57]
the virus before completed transformation , other causal processes seem more likely. Thus, compared with
EBV-positive HRS cells, EBV-negative HRS cells have significantly more cellular mutations, in particular in
negative regulators of the NF-κB pathway such as TNFAIP3 and NFKBIA, more chromosomal breakpoints
and aneuploid autosomes and almost never crippling immunoglobulin mutations .
[55]

EBV-positive cHL variants and modern treatment modalities
The generally poor prognosis of the non-negligible minority of patients with relapsed/refractory cHL has
spurred the development of novel treatment modalities, which are devised based on growing understanding
of the intricate biology of the interplay between the HRS cells and the TME. Complete reviews of cHL TME
and of the array of novel treatment modalities for cHL lie outside the scope of the present paper, and
interested readers are referred to Refs. [5,6,41,58] .

Aetiological heterogeneity of cHL may be clinically relevant in the context of such novel cHL treatment
approaches [6,12] . First, because EBV is present in the malignant cells in virus-positive cHL it makes sense to