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1606 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1607

for only 1 to 2 percent of the cellular composition, led to controversy these factors cause a global loss of the B-cell phenotype and aberrant
regarding the etiology and pathogenesis of cHL for more than 150 years. expression of genes of other cell lineages.
Molecular analyses of single cells obtained by microdissection led to the
discovery that cHL and NLPHL are both clonal disorders derived from
germinal center B cells, in most cases. The need to survive negative Genetic Alterations and Signaling Pathways
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selection in the germinal center, the determination of genetic alterations Because Hodgkin and Reed-Sternberg cells lack expression of func-
and constitutive activity of key signaling pathways, and the involve- tional B-cell surface receptors, rescue from apoptosis is probably an
ment of EBV in a subset of cases have led to hypotheses concerning the important mechanism of survival. 53,73 The most prevalent genetic lesions
malignant transformation events leading to the formation of Hodgkin/ in Hodgkin and Reed-Sternberg cells involve two signaling pathways:
Reed-Sternberg cells. Application of additional genomic technology Janus kinase (JAK)-STAT and nuclear factor-κB (NF-κB). Hodgkin and
promises to clarify the molecular changes underlying malignant trans- Reed-Sternberg cells have frequent gains in JAK2 and inactivation of the
formation and cellular proliferation. negative regulator of JAK-STAT signaling, suppressor of cytokine signal-
ing 1, resulting in enhanced cytokine signaling. 74,75 Genetic alterations
in NF-κB include gains and amplifications of the NF-κB transcrip-
Antigen Receptor Rearrangements tion factor REL in about half the cases of cHL. Somatic mutations
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Reed-Sternberg cells and their mononuclear variants demonstrate of the gene encoding the inhibitor of NF-κB (IκBα) occur in approx-
inconsistent lineage-specific antigen expression that is unlike any other imately 20 percent of cases. 77,78 Inactivating mutations and deletions
cell of the hematopoietic system. The origin of these cells was eventually of the gene encoding A20, a negative regulator of NF-κB, have been
determined through isolation of single cells by micromanipulation of found in approximately 40 percent of cases, nearly all of which were
histologic sections and analysis for immunoglobulin variable gene rear- EBV-negative. 79
rangements. 53,54 Nearly all Hodgkin and Reed-Sternberg cells have rear- Autocrine and paracrine signaling events also contribute to consti-
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ranged and somatically mutated immunoglobulin VH genes, indicating tutive activation of the JAK-STAT pathway and NF-κB transcription.
a germinal center or postgerminal center origin of classic Hodgkin and STAT factors are activated by autocrine means through expression
Reed-Sternberg cells. 55–57 Extrapolating from the fact that a subset of of interleukins (ILs) 13 and 21 and their receptors by Hodgkin and
these cells carries crippling mutations, it is possible that Hodgkin and Reed-Sternberg cells and augmented by NF-κB activity. 80–82 Receptor
Reed-Sternberg cells originate from a preapoptotic germinal center B tyrosine kinases expressed in these cells may also contribute to STAT
cell with unfavorable mutations that has escaped negative selection. activation. The tumor necrosis factor receptor family, which includes
Rare cases of cHL with a clonal T-cell receptor gene rearrangement have CD30, CD40, transmembrane activator, calcium modulator, and cyclo-
been observed. In contrast, single-cell analyses of NLPHL demon- philin ligand interactor (TACI), B-cell maturation antigen (BCMA),
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strated clonal immunoglobulin gene rearrangements with ongoing and receptor activator of NF-κB (RANK), is involved in NF-κB signal-
mutations, an intraclonal diversity consistent with a germinal center ing through interactions with the cHL microenvironment or in an auto-
origin of lymphocyte and histiocytic cells. 59–61 crine fashion. 83,84
Multiple receptor tyrosine kinases are aberrantly expressed in
Hodgkin and Reed-Sternberg cells, including platelet-derived growth
Reprogramming of Hodgkin and Reed-Sternberg Cells factor receptor-α. In addition, deregulated and constitutive acti-
Hodgkin and Reed-Sternberg cells show a global loss of their B-cell vation of the phosphoinositide 3′-kinase (PI3K)-AKT and extracellular
phenotype, retaining only B-cell features associated with their inter- signal-regulated kinase (ERK) pathways are implicated in Hodgkin and
action with T cells and their antigen-presenting function. Further- Reed-Sternberg cells. The activator protein 1 (AP1) transcription fac-
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more, Hodgkin and Reed-Sternberg cells express markers of other tors also appear to play a role, inducing target genes such as galectin 1
lineages, including T cells, dendritic cells, cytotoxic cells, and mye- and CD30 in Hodgkin and Reed-Sternberg cells.
loid cells. The lack of expression of numerous B-cell genes is the result Several factors point to the pathogenetic role of EBV in approxi-
of loss of transcription factor expression (OCT2, BOB1, PU.1) and mately 40 percent of classical cHL. The viral proteins latent membrane
epigenetic silencing. 63–65 The main B-cell lineage commitment factor, protein 1 (LMP1) and latent membrane protein 2 (LMP2), in particular,
PAX5, is typically expressed, but its target genes are downregulated. 66,67 appear to have hijacked signaling pathways to promote the survival of
Reduced expression of target genes likely reflects the fact that B-cell EBV-infected Hodgkin and Reed-Sternberg cells. LMP1 induces con-
genes are regulated by coordinated action of multiple transcription stitutive NF-κB signaling by mimicking the CD40 receptor and can
factors. activate JAK-STAT, PI3K, and AP1 signaling. LMP2 functions as a sur-
The heterogeneity of expression of myeloid, T-cell, dendritic cell, rogate for the B-cell receptor. The role of EBV in the pathogenesis of
and other genes by Hodgkin and Reed-Sternberg cells is the result of cHL also is supported by the findings that (1) there is an inverse rela-
many factors. Early B-cell factor 1 levels are low, de-repressing the tionship between expression of multiple receptor tyrosine kinases and
expression of T-cell and myeloid genes and lowering transcription of EBV expression, (2) there is an ability of EBV to rescue crippled germi-
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B-cell–specific genes. Notch 1, which plays a key role in promoting nal center B cells in the laboratory, (3) mutations preventing any B-cell
T-cell differentiation and inhibiting B-cell development, is expressed receptor expression are in EBV-positive Hodgkin and Reed-Sternberg
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in Hodgkin and Reed-Sternberg cells. Notch 1 also contributes to the cells, and (4) there is an inverse relationship between mutations reduc-
expression of GATA2, a transcription factor required for proliferation ing the expression of the NF-κB regulator A20 and EBV-positive Hodgkin
and survival of hematopoietic stem cells. The hematopoietic stem and Reed-Sternberg cells.
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cell regulator polycomb G proteins are also expressed by Hodgkin and Overall, genetic alterations involving the JAK-STAT and NF-κB
Reed-Sternberg cells and are thought to contribute to the expression of signaling pathways and further activation via autocrine or paracrine
markers of different hematopoietic lineages. The signal transducer and mechanisms interact to support the growth and survival of cHL
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activation of transcription factors (STAT) 5A and STAT5B are impli- cells. In the EBV-positive subset of patients, viral genes can provide
cated in Hodgkin and Reed-Sternberg reprogramming as they upreg- the pathogenetic function of genetic lesions found in EBV-negative
ulate CD30 and downregulate B-cell–receptor expression. Together, cases.
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