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Chapter 74 Origin of Hodgkin Lymphoma 1209

A second signaling pathway that shows constitutive activity in
The Role of Epstein-Barr Virus in Classical HRS cells and mutations in various pathway members is the JAK/
Hodgkin Lymphoma STAT pathway, the main pathway for cytokine signaling. Upon
activation of cytokine receptors, JAK kinases bind to the recep-
In about 40% of cases of classical HL in the Western world, and in tors and become activated. The activated JAKs then phosphorylate
about 90% of childhood HL cases in Central and Southern America, and thereby activate STAT factors, which upon phosphorylation
+
HRS cells are infected by EBV. Molecular analyses of EBV cases and dimerization translocate into the nucleus and function as
showed that EBV infection of HRS cells is a clonal event (i.e., transcription factors. Frequent genomic gains of JAK2 and also rare
EBV infected or was already present in the founder cell of the HRS translocations involving this gene have been detected in HRS cells.
cell clone). EBV-positive HRS cells typically show a latency II gene However, activating point mutations in the JAK2 gene, although
expression pattern characterized by expression of the EBV nuclear they are frequent in other types of hematologic diseases, are absent
antigen 1 (EBNA1) and the two latent membrane proteins 1 and in HRS cells. SOCS1, a main inhibitor of this signaling pathway, is
2a (LMP1 and LMP2a, respectively). EBNA1 is essential for the inactivated by somatic mutations in the HRS cells in about 40% of
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replication of the EBV episome in proliferating cells. LMP1 is an cases of classical HL. Recently, destructive mutations in the PTPN1
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oncogene, and one of its main functions is to cause constitutive gene were detected in HRS cells in 20% of cases. PTPN1 is a
NFκB activation by mimicking an activated CD40 receptor. LMP2a phosphatase that, among other functions, negatively regulates STAT
has a cytoplasmic motif that resembles the signaling motif of the activity.
BCR. LMP2a can, on the one hand, diminish BCR signaling by Notably, the genomic region on 9p24, which harbors the JAK2
recruiting BCR signaling components away from the BCR, but gene and shows gains in HRS cells, also encompasses the gene
on the other hand, it mimics a tonic BCR signal. Strikingly, all JMJD2C that encodes a histone demethylase, and the programmed
HRS cell clones with clearly destructive Ig V gene mutations that death 1 (PD-1) ligand genes PD-L1 and PD-L2. 24,25 PD-1 ligands
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prevent the expression of a BCR were found to be EBV-positive. inhibit PD-1–expressing T cells and may contribute to the immuno-
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Hence it appears that in GC B cell precursors of HRS cells that suppressive microenvironment in HL. A functional role of JMJD2C
acquired BCR-destructive mutations, EBV is essential to rescue these in HRS cells is indicated from the finding that downregulation of
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cells from apoptosis upon loss of BCR expression. This scenario is its expression in HL cell lines is toxic for these cells. Thus, a single
supported by studies showing that EBV can rescue BCR-deficient genetic lesion, the genomic gain on 9p24, affects four genes with
GC B cells from apoptosis, and that LMP2a has an important pathogenetic roles in HRS cells.
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role in this process. Whether the BCR-mimicking function is Because disturbed apoptosis seems to be a key aspect of classical
still important in the established HRS cell clone is unclear. The HL pathogenesis, numerous regulators of apoptosis were also studied
downregulation of most components of BCR signaling in HRS cells in HL cell lines and/or primary HRS cells. Mutations in the TP53
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indicates that LMP2a does not have this role in the established HRS gene were found in three HL cell lines and a few primary cases.
cell clone. Mutations in the CD95 gene were found in less than 10% of cases,
and no mutations were found in the CD95 signaling components
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Genetic Lesions in Hodgkin and Reed-Sternberg and CASP8, CASP10, and FADD. Moreover, no mutations were
detected in the proapoptotic gene BAD; mutations in ATM are also
Lymphocyte Predominant Cells very rare. 26
Chromosomal translocations, usually involving one of the Ig loci
The molecular analysis of HRS and LP cells for genetic lesions and an oncogene, are a hallmark of most B cell lymphomas. Also in
is hampered by the rarity of these cells. Nevertheless, we are now classical HL, chromosomal breaks involving the Ig loci were detected
aware of a number of transforming events, especially for HRS cells. by fluorescence in situ hybridization in about 20% of cases. However,
The recognition of constitutive activity of the NFκB transcription the translocation partners are in most cases unknown. In a few
factor, which is normally only transiently activated in lymphocytes, instances, BCL2, BCL3, BCL6, or MYC were identified as partners
prompted studies of whether gene mutations cause this deregulated of the translocations. This also includes composite lymphomas where
activity. Inactivating mutations in the gene NFKBIA, which encodes the clonally related classical HL and the B cell NHL were found to
the main inhibitor of NFκB (i.e., IκBα) were detected in 10% to 20% carry the identical translocation—for example, a BCL2-IgH translo-
1
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of cases of classical HL (Fig. 74.3). Also, mutations in the NFKBIE cation in a composite classical HL/follicular lymphoma. Notably,
gene were found. Genomic gains of the REL gene, encoding one of Ig locus–associated translocations usually function by causing deregu-
the NFκB factors, are present in about 40% of classical HL. Inactivat- lated expression of the translocated oncogene that has been brought
ing mutations in TNFAIP3, a further negative regulator of NFκB, under the control of the Ig regulatory elements, which are active
were detected in 40% of HRS cell clones. 20,21 Interestingly, most cases in normal B cells and B cell NHL. Because the Ig loci are largely
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with TNFAIP3 mutations were EBV-negative, suggesting that EBV silenced in HRS cells, it is still unclear whether the partner genes
infection and TNFAIP3 mutations are alternative mechanisms in of Ig locus–associated translocations in HRS cells are still active and
HL pathogenesis, thereby further supporting a pathogenetic role pathogenetically relevant. Perhaps the translocations were important
of EBV in HL development. Reestablishing wild-type TNFAIP3 during early stages of HRS cell pathogenesis, when the lymphoma
in HL cell lines reduced NFκB activity and survival, establishing precursor cells still had a B-cell gene expression program, but became
that TNFAIP3 functions as a tumor suppressor gene in this lym- less important during later stages of the multistep transformation
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phoma. For CYLD, another tumor suppressor gene and negative process. Alternatively, it should also be considered that translocations
regulator of NFκB, inactivating mutations were found in one HL might function by mechanisms other than Ig enhancer–driven onco-
cell line, but not in several primary cases of HL studied, indicating gene overexpression (e.g., promoter replacement or tumor suppressor
that mutations in this gene also occur in HRS cells, albeit at a gene inactivation).
low frequency. Rare mutations were recently also found in TRAF3, HRS cells show a heterogeneous pattern of major histocompat-
a negative regulator of the noncanonical NFκB pathway. Finally, ibility complex (MHC) class I and II expression. Recurrent transloca-
the NIK kinase gene (MAP3K4), encoding a major activating tions involving the MHC class II transactivator gene CIITA were
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factor for the noncanonical NFκB pathway, shows gains in 20% of found in about 15% of classical HL. These translocations involved
classical HL. heterogeneous partner genes and seemed to function by impairing
Although LP cells of NLPHL also show constitutive NFκB activ- CIITA function and hence dampening MHC class II expression.
2
ity, no destructive mutations were found in TNFAIP3 and NFKBIA The MHC class I component β-2-microglobulin (B2M) is mutated
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in these cells, and LP cells are not infected by EBV. In some NLPHL in more than half of classical HL according to a recent study.
REL gains were found. Thus, the mechanisms causing NFκB activa- Downmodulation of MHC class I is often a strategy of cancer cells
tion in HRS and LP cells are largely different. to evade attack by cytotoxic T cells.