The AP-1 transcription factor complex is a group of proteins capable of forming homodimers or heterodimers through their leucine-zipper domains. Different combinations of homodimers and heterodimers recognize different sequences in the promoters of AP-1 target genes that control cell proliferation and apoptosis thus contributing to oncogenesis.12
Of the proteins involved in AP-1, the Jun family, and particularly JunB, is the focus of this study.
Recent studies suggest a potential role for the AP-1 family of proteins, and in particular, the Jun family in the pathogenesis of Hodgkin lymphoma.4
In cultured Hodgkin and Reed–Sternberg cells, JunB was found to bind with the CD30
gene promoter. The CD30
gene promoter has three regions: a microsatellite sequence containing CCAT repeats, a core promoter with Sp-1 binding sites, and a downstream promoter element. In normal lymphoid cells, the microsatellite sequence suppresses the CD30
promoter. However, in Hodgkin and Reed– Sternberg cells JunB binds to an AP-1 site in the microsatellite sequence resulting in relief of repression of the CD30
As a result, CD30
gene expression is induced in Hodgkin and Reed–Sternberg cells.
Based on these data, we hypothesized that JunB might be overexpressed in other CD30+ lymphoproliferative disorders. We therefore assessed for JunB expression in a variety of CD30+ lymphomas including Hodgkin lymphoma and different types of CD30+ non-Hodgkin lymphoma. We also assessed cases of lymphomatoid papulosis. We found that 41 of 42 (98%) anaplastic large cell lymphoma cases were JunB+ (). In addition, all cases of classical Hodgkin lymphoma, CD30+ diffuse large B-cell lymphoma, cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis expressed JunB. Furthermore, we demonstrated coexpression of JunB and CD30 by the Hodgkin and Reed– Sternberg cells of classical Hodgkin lymphoma and the tumor cells of ALK+ anaplastic large cell lymphoma using a double immunostaining technique. By contrast, all CD30− cases of nodular lymphocyte-predominant Hodgkin lymphoma and diffuse large B-cell lymphoma were JunB− (). In all tumors assessed, we also identified rare CD30− small reactive lymphocytes that showed faint nuclear immunoreactivity for JunB indicating very low expression levels. The biologic significance of this finding is uncertain.
The results of this survey are in agreement with previously published data. Mathas et al4
have shown overexpression of JunB in Hodgkin lymphoma. Moreover, a subset of cutaneous T-cell lymphomas including cutaneous anaplastic large cell lymphoma tumors also express JunB.6
It is tempting to speculate that JunB, in CD30+ non-Hodgkin lymphomas and lymphomatoid papulosis, induces CD30 expression through interacting with the CD30 gene promoter, as has been shown in Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma.5
The underlying mechanism(s) of JunB overexpression in CD30+ lymphomas and lymphomatoid papulosis are largely unknown. Mao et al6
used comparative genomic hybridization to show gain of chromosomal material at the 19p13 locus, the site of the JunB
gene. They also used real-time PCR to show JunB
overexpression. Thus, gene amplification is one possibility. However, JunB
gene amplification has not yet been reported in Hodgkin lymphoma or other CD30+ non-Hodgkin lymphomas. Another theoretical mechanism would be accumulation of JunB protein due to decreased JunB degradation in these tumors. Recent studies provide insight into the mechanisms of c-Jun and JunB turnover.13,14
Interestingly, Gao et al14
demonstrated that JunB (and c-Jun) abundance can be regulated by extracellular stimuli in T-cells through Jun-N terminal kinase (JNK)-dependent phosphorylation of the novel E3 ligase Itch
The role of JunB-related AP-1 dimers in controlling cell proliferation is not completely understood. Although it has been suggested that JunB can form complexes with c-Jun that could suppress cell proliferation,2,15
the effects of JunB and its complexes with other AP-1 members on cell growth are still under investigation.1
Recent evidence in chronic myeloid leukemia suggests that JunB activity is significantly decreased as compared with the peripheral blood cells of healthy individuals, and that downregulation of JunB is the result of JunB
Furthermore, in mice JunB inactivation results in a myeloproliferative disorder resembling chronic myeloid leukemia.17
Szremska et al18
also have reported that transgenic expression of JunB inhibits proliferation and transformation in B but not T lymphocytes suggesting differential effects of JunB among different lymphocyte subtypes.
In summary, we have shown that JunB overexpression is a virtually constant feature in CD30+ lymphomas and in lymphomatoid papulosis. More mechanistic studies are needed to shed light on the molecular mechanisms underlying JunB upregulation as well the potential oncogenic role of JunB/CD30 signaling in these lymphomas.