Expression of the human germinal center–associated lymphoma (HGAL) protein identifies a subset of classic Hodgkin lymphoma of germinal center derivation and improved survival

Natkunam, Yasodha; Hsi, Eric D.; Aoun, Patricia; Song, Zhao; Elson, Paul; Pohlman, Brad; Naushad, Hina; Bast, Martin; Levy, Ronald; Lossos, Izidore S.

doi:10.1182/blood-2006-04-014977

Cited by 43 publications

(48 citation statements)

References 40 publications

(58 reference statements)

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“…43 STAT6 was found to be phosphorylated on Tyr641 and to be localized in the nucleus of the HRS cells in 78%-83% of the cases. 28,44 Our results implicate STAT6 as a mediator of LMP-1 expression in the EBV-carrying HRS cells. However, because LMP-1 is always expressed in all, but STAT6 is activated only in 78%-83% of the cHL cases, it is possible that in addition to STAT6 other mechanisms also operate in the EBNA-2-independent expression of LMP-1.…”

Section: Discussionmentioning

confidence: 72%

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Kis

Gerasimčik

Salamon

et al. 2011

Blood

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IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus of the Lymphocryptovirus genus that has succeeded to colonize Ͼ 90% of the adult population. 1 As a general characteristic of these viruses, they can all infect and immortalize B-lymphocytes in vitro. The in vitro EBV-infected B cells proliferate and give rise to lymphoblastoid cell lines (LCLs). The pattern of latent EBV gene expression seen in LCLs is referred to as the type III latency, in which 9 virally encoded proteins are expressed (EBV nuclear antigen 1-6 [EBNA1-6], Latent Membrane Protein-1 [LMP-1], LMP-2A, and LMP-2B). 1 Similarly to the EBV gene expression seen in LCLs, type III latent B cells were found in healthy persons during the primary infection 2 and the virus carrier state. 3 These cells are highly immunogenic and are eliminated by the cellular immune response. 4 After the primary infection the virus establishes a life-long infection in the memory B-cell reservoir, from where it is thought to reactivate and produce new progeny that are shed in the saliva. 1,5 In immunodeficient states, in which the cellular immune responses are compromised, the EBV-infected type III B cells can give rise to lymphoproliferations/lymphomas, as seen in the posttransplantation lymphoproliferations 6,7 and some AIDS lymphomas. 8 Depending on the histologic origin, the activation state, and the differentiation stage of the virus-carrying cells, EBV can adopt other viral gene expression patterns as well. 9 This is evidenced by the type I EBV gene expression seen in Burkitt lymphomas (BLs), primary effusion lymphomas, 10 and diffuse large B-cell lymphomas, whereby EBNA-1 is the only viral protein expressed. However, EBNA-1 is coexpressed with LMP-1 and LMP-2 in the EBV-carrying classical HL (cHL 11 ; type II latency), nasal natural killer/T-cell lymphoma, 12,13 some nasopharyngeal carcinomas (NPCs), 14,15 and peripheral T-cell lymphomas. 16 The expression of LMP-1 in type III latency is driven by the EBNA-2 protein. 1 The molecular mechanism of LMP-1 expression in type II latent cells, thus in the absence of EBNA-2, is only partially known. EBV-positive cHL is unique among the type II malignancies because all the Hodgkin/Reed-Sternberg (HRS) cells express high levels of LMP-1, whereas LMP-1 expression is heterogeneous in other tumors. 15 Not just the mechanism of LMP-1 expression in the HRS cells is unknown, but it is still an open question whether LMP-1 is needed for the survival or proliferation of these malignant cells. Although the type II EBV latency is seen in a proportion of cHLs, the available HL-derived cell lines are EBV negative. Thus, there is no in vitro system in which this type of virus-cell interaction can be studied.We have previously reported that exposure of the in vitro EBV-converted HL-derived cell line KMH2-EBV to CD40 ligand (CD40L) and interleukin-4 (IL-4) led to EBNA-2-independent expression of LMP-1. 17 In the continuation of this work we identify now IL-4, IL-13, and CD40L as potent inducers of LMP-1 not only Submitted January 21, 2010...

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Section: Discussionmentioning

confidence: 72%

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Kis

Gerasimčik

Salamon

et al. 2011

Blood

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“…1 H GAL, also known as germinal center-expressed transcript 2, was first identified in profiling studies as an interleukin (IL)-4-inducible gene whose expression in cases of diffuse large B-cell lymphoma (DLBCL) predicts for longer overall survival. 2,3 As the name suggests, A chief question now is whether HGAL works in concert with BCR signaling to block malignant cell migration. Critically, cytosolic HGAL is more efficient than wild-type HGAL in blocking cell migration.…”

mentioning

confidence: 99%

Enhancing BCR signals at the cell membrane

Slupsky

2015

Blood

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“…57 ). However, several studies show that in most cases BLIMP1 protein is only weakly expressed by HRS cells [57][58][59][60] . This could indicate that plasma cell differentiation is initiated in a fraction of HRS cells but remains abortive 58 .…”

Section: Blimp1 Is a Tumour Suppressor Genementioning

confidence: 99%

BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

Vrzalikova¹,

Woodman²,

Murray³

2012

BIOMED PAP

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Aims. The aim of this review was to summarize recent knowledge of the structure and function of a transcriptional repressor, B lymphocyte induced maturation protein 1 (BLIMP1) and its participation in the pathogenesis of B lymphomas. Methods and results. This review summarizes the structure and function of BLIMP1, its major target genes and its role as a tumour suppressor in B cell lymphomas. We review our recent data implicating the loss of BLIMP1α as an important step in the pathogenesis of the Epstein-Barr virus (EBV) associated B cell lymphomas. Conclusions. BLIMP1 is a transcriptional repressor essential for the differentiation of germinal centre (GC) B cells to plasma cells. The loss of BLIMP1 in GC B cells could contribute to the pathogenesis of EBV-associated lymphomas by preventing plasma cell differentiation and viral replication.

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Expression of the human germinal center–associated lymphoma (HGAL) protein identifies a subset of classic Hodgkin lymphoma of germinal center derivation and improved survival

Cited by 43 publications

References 40 publications

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Enhancing BCR signals at the cell membrane

BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

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