BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression

Maes, Brigitte; Demunter, Anouk; Peeters, Benjamin; Wolf-Peeters, Christiane De

doi:10.1182/blood.v99.4.1398

Cited by 70 publications

(61 citation statements)

References 28 publications

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“…79 Moderate nuclear expression of BCL10 is also observed in nearly 100% of MALT lymphomas with the other translocation, t(11;18). [80][81][82] On the basis of these findings, it has been suggested that the aberrant nuclear expression of BCL10 may be involved in the pathogenesis of MALT lymphoma.…”

Section: Molecular Pathogenesis Of Malt Lymphoma M Nakagawa Et Almentioning

confidence: 99%

“…113 Several immunohistological studies have demonstrated the subcellular localization of BCL10 in MALT lymphoma cases. [79][80][81] However, the mechanism of this localization of BCL10 is not yet fully understood, thus prompting us to examine the subcellular localization of BCL10 in COS7 cells, where we found that BCL10 was localized in both cytoplasm and nucleus. 113 Our examination of subcellular localization of both BCL10 and MALT1 in a co-transfection system found that these two proteins are colocalized in the cytoplasm only, but, intriguingly, that the NES-specific inhibitor, leptomycin B, treatment has changed their subcellular localization from the cytoplasm to the nucleus.…”

Section: Two Signaling Pathways Underlying the Antiapoptotic Effect Bmentioning

confidence: 99%

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Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

2006

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At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-jB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-jB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-jB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-jB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10. Leukemia (2006) 20, 929-936.

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Section: Molecular Pathogenesis Of Malt Lymphoma M Nakagawa Et Almentioning

confidence: 99%

Section: Two Signaling Pathways Underlying the Antiapoptotic Effect Bmentioning

confidence: 99%

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

2006

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“…Part of these cases was included in previous studies. 5,7,9,[14][15][16][17] Gastric endoscopic biopsies were included in this study on condition that clonal Ig heavy chain rearrangement was demonstrated to support the diagnosis of a MALT lymphoma. All cases were reviewed and diagnosed as extranodal marginal zone lymphomas according to the recent criteria of the WHO.…”

Section: Case Selectionmentioning

confidence: 99%

“…Nuclear BCL10 expression has been linked to the presence of t(1;14)(p22;q32) or t(11;18)(q21;q21), but the mechanisms of the aberrant nuclear localisation of BCL10 in malignant B cells remain unclear. 5,6 The MALT1 gene is directly involved in the MALT lymphoma-associated chromosomal translocations t(11;18)(q21;q21) and t(14;18)(q32;q21). The first translocation is the most common structural chromosomal abnormality in gastric MALT lymphoma.…”

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confidence: 99%

MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells

et al. 2006

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Among the genetic abnormalities reported to occur in mucosa-associated lymphoid tissue (MALT) lymphomas, the three translocations t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are of particular interest because they appear to be specific for, or at least closely related to this type of B-cell non-Hodgkin's lymphoma. These translocations affect the MALT1 (18q21) and BCL10 (1p22) genes. We retrieved 77 consecutive biopsies of MALT lymphomas (documented with frozen material) over a 10-year period and investigated these cases for the presence of these three translocations with fluorescence in situ hybridisation, along with the immunohistochemical analysis of the intracellular localisation of the BCL10 protein. The above-listed translocations occurred mutually exclusive and were detected in 10, 1 and 3% of the cases, respectively (the latter incidence being much lower than in the previously reported studies by one single group). These genetic rearrangements corresponded well with the aberrant subcellular localisation of the BCL10 protein as found by immunohistochemistry: t(11;18)(q21;q21) and (1;14)(p22;q32) were marked by a, respectively, moderate to strong nuclear BCL10 staining pattern while t(14;18)(q32;q21)-positive MALT lymphomas were characterised by a perinuclear BCL10 staining pattern. This study further supports the close interaction between the MALT1 and BCL10 proteins in the pathogenesis of MALT lymphomas and may indicate that BCL10 immunohistochemistry is a simple technique to identify those MALT lymphoma cases with an underlying genetic aberration. 1 It is characterised by several recurrent chromosomal aberrations including t(1;14)(p22;q32), t(11;18) (q21;q21), t(14;18)(q32;q21), t(3;14)(p13;q32), and by trisomy 3 and 18.The t(1;14)(p22;q32) results in deregulation of the BCL10 gene after its juxtaposition with the regulatory sequences of the immunoglobulin heavy chain gene cluster (IGH).2 BCL10 encodes a 32 kDa apoptosis regulatory molecule, characterised by an amino-terminal caspase recruit domain (CARD) motif and a Ser/Thr-rich carboxyl terminus of unknown function.3 Monoclonal antibodies raised against the BCL10 protein demonstrate cytoplasmic expression of BCL10 in lymphoid tissue and in breast epithelium. 4 In normal lymphoid tissue, BCL10 is expressed exclusively in the cytoplasm of germinal centre and marginal zone B cells. In MALT lymphomas, the BCL10 expression might be observed in the nucleus as well. Nuclear BCL10 expression has been linked to the presence of t(1;14)(p22;q32) or t(11;18)(q21;q21), but the mechanisms of the aberrant nuclear localisation of BCL10 in malignant B cells remain unclear. 5,6The MALT1 gene is directly involved in the MALT lymphoma-associated chromosomal translocations t(11;18)(q21;q21) and t(14;18)(q32;q21). The first translocation is the most common structural chromosomal abnormality in gastric MALT lymphoma. 7,8 It leads to the generation of a fusion protein comprising the three BIR (baculovirus inhibitor of apoptosis protein repeat) domains present in...

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“…Actin polymerization then appeared to be a key factor in the migration of microclusters. Interestingly, the adaptor ADAP is linked to the actin cytoskeleton and, upon antigenic stimulation, is recruited to the actin-rich periphery of the immune synapse, where it associates with the microtubule motor dynein [107]. Furthermore, ADAP was shown to play a role in the relocation of the MTOC to the IS through its interaction with dynein.…”

Section: Molecular Requirements For the Polarization Of The Ismentioning

confidence: 99%

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

Messali¹,

Génin

Weil³

2013

J Leuk

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The adaptive immune response is initiated when microbial or tumor-specific molecules are recognized by antigen receptors present at lymphocyte cell surface. Engagement of these immunoreceptors induces signaling cascades that ultimately activate the transcription factors NF-κB (Nuclear Factor-κB) and NFAT (nuclear factor of activated T-cells) responsible for the establishment of gene expression programs controlling the stimulation, proliferation and survival of activated lymphocytes. Cloning the products of three distinct translocation events found in lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) led to the identification and characterization of a novel NF-κB-activating complex following antigenic stimulation composed by the CARMA1, BCL10, and MALT1 proteins and called the CBM complex. Since the identification of this complex, other regulatory components were discovered which greatly improve our understanding of this signaling pathways.Interestingly, CBM complex activity is not only altered in MALT lymphomas but also in a subtype of activated B cell-like (ABC) of diffuse large B-cell (DLBCL) lymphoma. In this review, we described the key players involved in antigen-induced NF-κB activation and covered the recent advances in the molecular mechanisms that are responsible for the regulation of the components of the CBM complex. Understanding these mechanisms is critical for the elucidation of the role of this NF-κB signaling network in both normal and pathologic conditions and we described how dysregulation of this network leads to the uncontrolled activation of NF-κB and development of two particular subtypes of human B cell lymphomas: the MALT and the DLBCL lymphomas. DAP12) [1]. Engagement of these receptors initiate a signal-activation cascade that includes phosphorylation of two specific tyrosine residues located in the ITAM by the Src family kinases [1]. Tyrosine kinase Syk or ZAP-70 (zeta-chain-associated protein 70 kD) are then recruited to the phosphorylated ITAM through their tandem Src homology 2 (SH2) regions, initiating downstream signaling cascades that lead to the stimulation of mitogen-activated protein kinase (MAPK) activities and ultimately to the activation of the transcription factors NF-κB and NF-AT (nuclear factor of activated T-cells).An outstanding issue of lymphocyte activation was the identification of a complex of proteins comprising CARMA1, BCL10 and MALT1 (also called the CBM complex) as critical regulators of the immunoreceptor signaling pathways. In this review, we will focus on the recent advances concerning the role of the CBM function in antigen-induced NF-κB signaling and detail how this pathway may selectively become dysregulated in lymphoma. The key players of antigen-mediated NF-κB activationAntigen receptor activation initiates a phosphorylation cascade that promotes assembly of the CBM signalosome complex composed of CARMA1, BCL10, and MALT1 that ultimately activates the NEMO/ IKK complex to promote NF-κB transcription (Figure 1). In this

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BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression

Cited by 70 publications

References 28 publications

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

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