Comment on Ushmorov et al, page 2493
In this issue of Blood, Ushmorov and colleagues report on epigenetic aberrations involved in the pathophysiology of classical Hodgkin lymphoma (cHL). The combined down-regulation of a few “master” transcription factors may be the cause of a concerted global silencing of a regulatory network implicated in BCR signaling.
In recent years, the concept of “loss of the B-cell identity” of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) has evolved as the main hallmark of this tumor. Several reports have repeatedly documented this singularity at the protein level using immunohistochemical studies in primary tumors, and also at the RNA level by gene expression studies on cHL-derived cell lines.1-3 This aberrant phenotype is unique among B-cell neoplasms, and comprises the simultaneous loss of expression of many specific B-cell surface markers, B-cell–specific transcription factors, and, above all, the main attribute of the B-cell lineage: the B-cell receptor (BCR) and its signaling components. How these global down-regulations of proteins might happen in this tumor is a mystery.
Mutations and gene translocations are rare in cHL; therefore, epigenetic modifications represent reasonable targets for research. In the current issue of Blood, Ushmorov and colleagues elegantly demonstrate gene silencing associated with gene promoter hypermethylation as a common cause for this aberrant phenotype in cHL-derived cell lines and also in HRS cells microdissected from primary tumors, identifying CD19, CD20, CD79a, SYK, PU.1, BOB.1, BCMA, and LCK as targets for epigenetic modification, and finally illustrating a concerted global silencing of a regulatory network.
In this issue of Blood, Ushmorov and colleagues describe the existence of specific hierarchies in this process, which occurs in a well-ordered (instead of stochastic) way. Thus, they present convincing evidence that loss of Oct2 and BOB.1/OBF.1 expression is earlier than loss of PU.1, playing a dominant role in the hierarchy of B-cell transcription factors. Likewise, they illustrate an “ongoing” methylation process for many of these genes. Thus, silencing of the B-cell–specific genes may be the consequence of a compromised regulatory network, where down-regulation of a few “master” transcription factors results in nonrandom silencing of numerous functionally or structurally related genes.
Many questions remain unanswered, however. As BCR represents the major survival signaling pathway in normal B-cells, the global down-regulation of its components in HRS cells seems to be contradictory, unless the acquisition of other survival programs (such as constitutive nuclear factor [NF]–κB activation),4 would obviate the necessity of the normal B-cell gene program and thus initiate a selection process against maintaining such a program.
In this scenario, it is tempting to speculate that the silencing of the expression of the BCR-related genes is a benefit for HRS cells. Ushmorov and colleagues affirm that “given the described roles of several BCR signaling components in regulation not only of B-cell proliferation but also of B-cell apoptosis, silencing the expression of these genes might actually be a selective advantage for HRS.” Different reports have also shown that the levels of expression of BCR-signaling genes could be opposite of the levels of NF-κB activation, as is the case of mediastinal large B-cell lymphoma,5 a tumor closely related to cHL. The findings of Ushmorov and colleagues are consistent with this selected loss of B-cell–specific gene expression as a surrogate of a transformed program, supporting the concept of epigenetic loss of B-cell identity as part of the neoplastic transformation process leading to cHL.
Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. Thus, a better understanding of the transforming mechanisms and associated aberrations in HRS cells opens the possibility to design new therapeutic strategies for cHL patients. ▪