Nuclear BCL-10 expression is common in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and does not correlate with p65 NF-κB activation

Merzianu, Mihai; Jiang, Liuyan; Lin, Pei; Wang, Xuemei; Weber, Donna M.; Vadhan‐Raj, Saroj; Nguyen, Martin; Medeiros, L. Jeffrey; Bueso‐Ramos, Carlos E.

doi:10.1038/modpathol.3800609

Cited by 16 publications

(15 citation statements)

References 38 publications

(50 reference statements)

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“…BCL-10 immunostaining in breast MALT lymphomas is discordant with these results, but nuclear BCL-10 staining has been reported in extra-mammary MALT lymphomas without the t(11;18) in other studies. 14,[17][18][19] Thus, our results support those of others and suggest that moderate nuclear BCL-10 immunostaining overestimates the percentage of neoplasms that carry MALT1 gene rearrangements. The BCL-10 and NF-kB data in primary breast diffuse large B-cell lymphomas shows that this group is heterogeneous, with most cases showing weak cytoplasmic BCL-10 staining and a subset of cases showing evidence of NF-kB activation, unlike breast MALT lymphomas.…”

Section: Discussionsupporting

confidence: 81%

“…The explanation for this apparent discordance is uncertain, but others have reported moderate nuclear BCL-10 immunoreactivity in MALT lymphomas without the t (11;18). 14,[16][17][18][19] More specifically, although moderate nuclear staining for BCL-10 is usually observed in MALT lymphomas with the t(11;18), up to 20-50% of MALT lymphomas without the t(11;18) also show moderate nuclear BCL-10 positivity. Thus, although BCL-10 immunostaining can be used as an initial screen for the t(11;18) in MALT lymphomas, the presence of BCL-10 nuclear expression should not be used as a surrogate for the presence of the t (11;18).…”

Section: Discussionmentioning

confidence: 99%

“…Positive controls used in this study were cases of MALT lymphoma with rearrangements involving 18q21 identified by conventional cytogenetics and FISH previously. 14 …”

Section: Fish Analysismentioning

confidence: 99%

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MALT1 gene rearrangements and NF-κB activation involving p65 and p50 are absent or rare in primary MALT lymphomas of the breast

et al. 2006

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Mucosa associated lymphoid tissue (MALT) lymphomas arising in the breast are uncommon and few cases have been assessed for MALT lymphoma-associated translocations, BCL-10 expression, or NF-jB activation. In this study, we analyzed eight cases of primary breast MALT lymphoma. We also included 14 cases of primary breast diffuse large B-cell lymphoma since some of these may represent transformation of MALT lymphoma, known to occur at extra-mammary MALT sites. All cases were assessed for MALT1 gene rearrangements by fluorescence in situ hybridization (FISH). Using immunohistochemical methods, all cases were assessed for BCL-10, and subsets were assessed for NF-jB p65 and p50. None of the cases had MALT1 gene rearrangements by FISH. Of eight MALT lymphomas, BCL-10 was positive in seven (88%), with moderate nuclear and cytoplasmic staining in six, and a weak cytoplasmic staining in one. NF-jB p65 (n ¼ 8) and p50 (n ¼ 5) were negative or showed only cytoplasmic staining (ie inactivated) in all cases. Of 14 diffuse large B-cell lymphoma cases, BCL-10 was positive in 12 (87%), with weak-to-moderate cytoplasmic staining in 10, weak cytoplasmic and focally nuclear staining in one, and a moderate-to-strong nuclear and cytoplasmic staining in one. NF-jB p65 (n ¼ 11) showed cytoplasmic staining in all cases, whereas p50 (n ¼ 8) showed nuclear positivity (ie activated) in two (25%) cases. We conclude that MALT1 gene rearrangements are absent or rare in primary breast MALT lymphoma and diffuse large B-cell lymphoma. In MALT lymphomas, the moderate BCL-10 nuclear expression in six neoplasms is inconsistent with the FISH results, suggesting that BCL-10 immunostaining overestimates the frequency of MALT1 gene rearrangements. We also could not demonstrate NF-jB activation using nuclear staining for p65 and p50. In contrast, breast diffuse large B-cell lymphomas are heterogeneous. Weak cytoplasmic BCL-10 staining in most cases and evidence of NF-jB p50 activation in a subset differs from breast MALT lymphomas.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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MALT1 gene rearrangements and NF-κB activation involving p65 and p50 are absent or rare in primary MALT lymphomas of the breast

et al. 2006

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“…Ours and other previous findings have shown that different domains at HBx-COOH may represent various mechanisms, and the mutations may directly affect the proliferation and invasion by regulating the cell cycle and inducing the expression of p21 WAF1 , p14 ARF and MDM2 (13). This supports the hypothesis that deleted forms of HBx may contribute to liver carcinogenesis (13,(30)(31)(32). Our previous findings also demonstrated that CENP-A overexpression was correlated with serum HBsAg states in HCC patients (16).…”

Section: Discussionsupporting

confidence: 73%

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

Liu

Li²,

Zhang³

et al. 2011

Oncol Rep

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Abstract. The carcinogenic role of hepatitis B virus x protein (HBx) in hepatocellular carcinoma (HCC) remains largely unknown. Centromere protein A (CENP-A) has been found to be frequently overexpressed in HCC. In the present study, we aimed to investigate the role of HBx in regulating CENP-A activity in HCC carcinogenesis. CENP-A expression was examined and the HBx gene was sequenced in 20 HBsAgpositive HCC patients and corresponding non-cancerous liver tissues. The influence of HBx mutants on CENP-A expression in HepG2 cells was analyzed by a series of assays. We found that CENP-A expression was significantly elevated in HCC tissues. HBx deletion, especially the COOH-terminal deletion of HBx is a frequent event in HBV-associated HCC tissues. A positive correlation was found between CENP-A expression and HBx COOH mutation in HCC tissues. HBx mutant increased the expression of the CENP-A mRNA and protein compared with full-length HBx. However, HBx did not directly interact with CENP-A. It is concluded that overexpression of CENP-A is closely associated with HBx COOH mutation in HCC. HBx mutant can increase CENP-A expression, probably through a mechanism independent of their physical combination, and thereby it may represent a potential therapeutic strategy for HCC.

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“…9,10 Data for its role in WM are limited, but there is some evidence to suggest that NF-B is activated in WM cells. 11,12 The PI3K/Akt pathway acts as a critical regulator of cell survival by stimulating cell proliferation and inhibiting apoptosis, [13][14][15] and has been implicated in the pathogenesis of various cancers, including lymphoproliferative disorders. [16][17][18] Akt indirectly activates NF-B through direct phosphorylation and activation of IB kinase alpha (IKK␣), thereby inducing degradation of NF-B inhibitor alpha (IB␣) by the ubiquitineproteasome pathway.…”

Section: Introductionmentioning

confidence: 99%

Targeting NF-κB in Waldenstrom macroglobulinemia

Leleu

Eeckhoute

Jia

et al. 2008

Blood

101

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The nuclear factor-B (NF-B) pathway has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of IntroductionWaldenstrom macroglobulinemia (WM) is a low-grade lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow (BM) and a serum monoclonal immunoglobulin M protein in the circulation. 1,2 Although indolent, it remains incurable and most patients die of disease progression with a median overall survival of 5 to 6 years. 3 Therefore, there is an urgent need for rationally designed combinations of therapy in WM. Recent genomic and proteomic studies have demonstrated that several signaling pathways play an important role in the pathogenesis of WM compared with normal controls or other B-cell malignancies, including the nuclear factor-B (NF-B) and PI3K/Akt pathways. 4 The NF-B signaling pathway regulates the survival of normal and malignant B cells by controlling the expression of cell death regulatory genes. 5,6 Depending on the cellular context, tumor necrosis factor alpha (TNF␣) signaling and other stimuli activate the NF-B pathway and augment the transcription of NF-B target genes. 5 These NF-B target genes enhance cell survival, inhibit apoptosis, and limit the activity of proapoptotic BCL2 family members, in addition to multiple other effects. 5 The NF-B pathway undergoes a very tight, although complex, regulatory mechanism in which NF-B controls its inhibitor IB␣ transcription and in stabilizing IB proteins. 7,8 The NF-B pathway-central role in plasma cell dyscrasia tumorigenesis has been recognized for a long time, partly through induction of cytokines and growth factors that promote tumor cell growth and survival. 9,10 Data for its role in WM are limited, but there is some evidence to suggest that NF-B is activated in WM cells. 11,12 The PI3K/Akt pathway acts as a critical regulator of cell survival by stimulating cell proliferation and inhibiting apoptosis, [13][14][15] and has been implicated in the pathogenesis of various cancers, including lymphoproliferative disorders. [16][17][18] Akt indirectly activates NF-B through direct phosphorylation and activation of IB kinase alpha (IKK␣), thereby inducing degradation of NF-B inhibitor alpha (IB␣) by the ubiquitineproteasome pathway. 9,10 The degradation of cellular proteins is critical for n...

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Nuclear BCL-10 expression is common in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and does not correlate with p65 NF-κB activation

Cited by 16 publications

References 38 publications

MALT1 gene rearrangements and NF-κB activation involving p65 and p50 are absent or rare in primary MALT lymphomas of the breast

MALT1 gene rearrangements and NF-κB activation involving p65 and p50 are absent or rare in primary MALT lymphomas of the breast

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

Targeting NF-κB in Waldenstrom macroglobulinemia

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