High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease

Nishikori, Momoko; Maesako, Yoshitomo; Ueda, Chiyoko; Kurata, Michio; Uchiyama, Takashi; Ohno, Hitoshi

doi:10.1182/blood-2002-08-2464

Cited by 52 publications

(50 citation statements)

References 47 publications

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“…High BCL3 expression has also been reported in a subgroup of anaplastic large-cell lymphoma (Nishikori et al, 2003). Consistent with an oncogenic function, BCL3 can directly transform cells and induce tumor growth in vivo (Viatour et al, 2004).…”

Section: Introductionmentioning

confidence: 74%

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IjB family protein that is involved in transcriptional regulation of a number of NF-jB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-jB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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Section: Introductionmentioning

confidence: 74%

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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“…19 In anaplastic large-cell lymphoma, a prior study has shown that BCL-3 expression and both genetic and epigenetic modifications of the bcl-3 gene may be associated with oncogenesis. 13 Izban and colleagues 30 have reported that NF-kB p65 is expressed in cutaneous T-cell lymphoma cell lines and neoplastic T lymphocytes from patient samples of mycosis fungoides, and they also showed that nuclear NF-kB activity is required for cell survival and resistance to apoptosis in the neoplastic cells. Although BCL-3 has a strong preference towards p50 and p52 It is also known that stimuli such as tumor necrosis factor a, interleukin1b not only cause nuclear accumulation of p50-p65 heterodimers, but also induce formation of BCL-3-p50 complexes.…”

Section: Bcl-3 In Lymphomasmentioning

confidence: 99%

“…For example, two recent studies have shown high levels of BCL-3 expression in ALKpositive anaplastic large-cell lymphoma. 13,14 However, presence or absence of BCL-3 expression is unknown for most of the wide variety of lymphoma types defined in the recently published World Health Organization (WHO) classification. 15 In this study, we used an immunohistochemical method and a commercially available monoclonal antibody specific for BCL-3 to assess for expression in 353 cases of non-Hodgkin lymphoma and Hodgkin lymphoma.…”

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confidence: 99%

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases

et al. 2004

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The bcl-3 gene at chromosome 19q13 encodes a member of the IjB family involved in regulating the NFjB pathway. Originally identified by its involvement in the rare t(14:19)(q32;q13), BCL-3 expression has never been analyzed in a wide variety of lymphomas. We assessed BCL-3 expression in 353 cases of non-Hodgkin lymphoma and Hodgkin lymphoma using formalin-fixed, paraffin-embedded tissue specimens, a monoclonal antibody specific for BCL-3, and immunohistochemical methods. Of 172 B-cell lymphomas, 10 (6%) were positive for BCL-3, including six of 23 (26%) diffuse large B-cell lymphoma, one of 17 (6%) small lymphocytic lymphoma, one of 26 (4%) follicular lymphoma, and two of 49 (4%) mantle cell lymphoma. All other B-cell neoplasms were negative, including marginal zone lymphoma (n ¼ 24, 11 extranodal, nine nodal, four splenic), Burkitt lymphoma (n ¼ 10), lymphoplasmacytic lymphoma (n ¼ 10), lymphoblastic lymphoma (n ¼ 8), and plasmacytoma (n ¼ 5). Of 111 T/NK-cell lymphomas, 25 (23%) were positive for BCL-3, including 13 of 40 (32%) anaplastic large-cell lymphoma, three of 10 (30%) angioimmunoblastic T-cell lymphoma, two of eight (25%) extranodal NK/T-cell lymphoma of nasal type, three of 12 (25%) mycosis fungoides, one of five (20%) enteropathy-type T-cell lymphoma, and two of 21 (10%) peripheral T-cell lymphoma unspecified. All other T-cell neoplasms were negative, including lymphoblastic lymphoma (n ¼ 6), prolymphocytic leukemia (n ¼ 6), and subcutaneous panniculitis-like T-cell lymphoma (n ¼ 3). Of 70 Hodgkin lymphomas, of all types, 29 (41%) were positive for BCL-3. The relatively high frequency of BCL-3 expression in some non-Hodgkin and Hodgkin lymphoma types raises the possibility that BCL-3 is involved in the pathogenesis of these tumors, and may be a target of new therapies.

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“…30 Bcl-3 protein levels are high in such leukemias, as well as in some lymphomas, including a subgroup of anaplastic large lymphoma (ACLC) with t(2;5)(q23;q35), where a combination of genetic and epigenetic modifications is supposed to lead to bcl-3 overexpression. [31][32] Bcl-3 protein shares with IkB family proteins the presence of ankyrin domains; however, at variance with the other IkB proteins, it is mainly nucleoplasmic and can enhance NFkB-dependent transcription (33)(34)(35). Indeed, in the cell nucleus, Bcl-3 can either interact with suppressor p50 homodimers and remove them from DNA, or bind to p52 homodimers to coactivate transcription.…”

mentioning

confidence: 99%

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

et al. 2003

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The activity of NF-jB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfjb or ijB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-jB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-jB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-jB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NFjB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-jB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-jB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-jB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow. Regulation of apoptosis by NF-jB/Rel factors NF-kB/Rel transcription factors are dimers of proteins (p50/p105 or NF-kB1, p52/p100 or NF-kB2, p65 or RelA, c-Rel and RelB) containing an approximately 300 amino-acid REL homology domain (RHD), which mediates protein dimerization and binding to DNA. 1 The RHD is also involved in interacting with the ankyrin repeats of IkB, a family of proteins coevolved with NF-kB/Rel. 1,2 NF-kB/Rel dimers are retained in the cytoplasm of several cell types by inhibitors of the IkB family. Growth factors, cytokines, hormones or other agents can induce, through the IKK (IkB-kinase) cascade or other kinases, 1,2 the phosphorylation and ubiquitin-mediated degradation of the IkB proteins, allowing the NF-kB/Rel dimers to reach the nucleus. 3 NF-kB/Rel activation is also induced by stress stimuli that provoke increases in the intracellular concentration of reactive oxygen species (ROS), imbalance in calcium ions fluxes and/or accumulation of unfolded proteins in the endoplasmic reticulum (RE). Such events trigger the activation of stress kinases and other modulators, which ultimately lead to IkB degradation. [1][2][3]

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High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease

Cited by 52 publications

References 47 publications

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

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