Somatic hypermutation of IGVH genes and aberrant somatic hypermutation in follicular lymphoma without BCL-2 gene rearrangement and expression

Gagyi, Eva; Balogh, Zsuzsanna; Bödör, Csaba; Tímár, Botond; Reiniger, Lilla; Deák, Linda; Csomor, Judit; Csernus, Balázs; Szepesi, Ágota; Matolcsy, András

doi:10.3324/haematol.13239

Cited by 23 publications

(18 citation statements)

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“…First, although it is rare, MZL may develop from t(14;18)-bearing cells, as reported here for a case with SMZL and in other reports of IGH/BCL2 MALT lymphoma. Second, the IGHV mutation load was lower in most of the t(14;18)-positive CLL cases than in the GC-derived B-cell lymphoma cases (a median mutation load of 92·1% vs. 88·0%) (Gagyi et al, 2008). Third, the analysed FAS loci were unmutated in all of the CLL cases with an IGH/BCL2 translocation (Müschen et al, 2000).…”

Section: Discussionmentioning

confidence: 94%

In non‐follicular lymphoproliferative disorders, IGH/BCL2‐fusion is not restricted to chronic lymphocytic leukaemia

et al. 2012

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SummaryThe translocation t(14;18) and its t(2;18) and t(18,22) variants, which involve the BCL2 genetic hallmark for follicular lymphoma (FL), have been reported in several cases of chronic B‐cell lymphoproliferative disease (CLPD) and frequently in chronic lymphocytic leukaemia (CLL). We describe here the clinical, morphological, immunological, cytogenetic and molecular findings from 37 cases of t(14;18)‐positive CLPD, identified from our series of non‐FL B‐cell neoplasms (n = 993) that were routinely analysed in peripheral blood by conventional cytogenetics analyses. The FL diagnosis was excluded by morphology and immunology (the samples were CD10 negative in all cases). The BCL2 translocations were observed in 22 CLL cases, including 7 monoclonal B‐cell lymphocytosis (MBL) cases re‐classified according to the new International Workshop on CLL criteria, six small lymphocytic lymphoma (SLL) cases, 1 splenic marginal zone lymphoma (SMZL) case and eight cases of unclassifiable CLPD with overlapping CLL/MZL features. In the CLL cases, the IGH/BCL2 fusion was remarkably associated with trisomy 12 (13/22) and mutated IGHV status (20/21) and did not affect the outcome. Moreover, most of these CLLs harboured a low mutation load of BCL6 gene and unmutated FAS (CD95) loci, which points to a post–germinal‐centre cellular origin.

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Section: Discussionmentioning

confidence: 94%

In non‐follicular lymphoproliferative disorders, IGH/BCL2‐fusion is not restricted to chronic lymphocytic leukaemia

et al. 2012

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“…We and others 4,6,7 have previously investigated the morphologic and molecular features of t(14;18)-negative FLs. Current evidence suggests that these lymphomas share many morphologic, genetic, and molecular characteristics with their t(14;18)-positive counterparts that would not justify a diagnosis other than FL (eg, marginal zone lymphoma) according to currently established WHO guidelines.…”

Section: Introductionmentioning

confidence: 99%

“…It is unclear whether they differ in their clinical behavior and whether these lymphomas display pathogenetic features equivalent to BCL2 deregulation in t(14;18)-positive FLs. Such molecular events in t(14;18)-negative FLs, however, have not been identified as of yet.We and others 4,6,7 have previously investigated the morphologic and molecular features of t(14;18)-negative FLs. Current evidence suggests that these lymphomas share many morphologic, genetic, and molecular characteristics with their t(14;18)-positive counterparts that would not justify a diagnosis other than FL (eg, marginal zone lymphoma) according to currently established WHO guidelines.…”

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confidence: 99%

MicroRNA profiles of t(14;18)–negative follicular lymphoma support a late germinal center B-cell phenotype

Leich

Zamò

Horn

et al. 2011

Blood

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IntroductionFollicular lymphoma (FL) constitutes the second most common B-cell malignancy among B-cell non-Hodgkin lymphomas (BNHLs). 1 It is considered an indolent lymphoma with a median overall survival of 8 to 10 years, but with an upward trend toward even further increased survival times because of more recent, improved treatment regimens. 2,3 FL is currently viewed as a germinal center (GC) B-cell derived lymphoma. Its origin in the GC influences the molecular characteristics but is also reflected at the morphologic level, as FL usually forms atypical follicles that in many aspects mimic their physiologic counterparts and typically express GC-associated B-cell markers, such as CD10, BCL6, and IRF-8. 1 Approximately 90% of FLs carry the translocation t(14;18)(q32;q21), leading to deregulated and aberrant expression of the antiapoptotic protein BCL2. Even with advanced, high-resolution techniques, however, a molecular rearrangement of the BCL2 gene cannot be detected in 10% of FLs, 4,5 raising the question of whether these cases belong to the biologic spectrum of "conventional" FLs. It is unclear whether they differ in their clinical behavior and whether these lymphomas display pathogenetic features equivalent to BCL2 deregulation in t(14;18)-positive FLs. Such molecular events in t(14;18)-negative FLs, however, have not been identified as of yet.We and others 4,6,7 have previously investigated the morphologic and molecular features of t(14;18)-negative FLs. Current evidence suggests that these lymphomas share many morphologic, genetic, and molecular characteristics with their t(14;18)-positive counterparts that would not justify a diagnosis other than FL (eg, marginal zone lymphoma) according to currently established WHO guidelines. In this study, we performed microRNA (miR) profiling of t(14;18)-negative FLs to further characterize this FL subgroup on the molecular level and to substantiate findings previously derived from gene expression profiling experiments. miR are transcriptional and translational inhibitors with important functions in physiologic cellular processes, but there is increasing evidence that they also play a pivotal role in the oncogenic evolution in many types of cancer. 8 In FLs, data on miR profiles are scarce, 9,10 and t(14;18)-negative FLs have not been characterized yet. We here show that t(14;18)-negative FLs have distinct miR expression profiles that are in support of a late GC B-cell phenotype and that may be associated with particular biologic properties of this Submitted June 28, 2011; accepted September 18, 2011. Prepublished online as Blood First Edition paper, September 29, 2011; DOI 10.1182 DOI 10. /blood-2011 *G.O., L.H., and A.R. contributed equally to this study as co-senior authors.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 5550BLOOD, 17 N...

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“…Rare BCL6 and FAS mutations present in GC but not naive B cells were ascribed as byproducts of "normal" SHM, 11,12 whereas mutations in PIM1, c-MYC, RHOH, and PAX5, present in several B-cell lymphomas but not in normal GC B cells, were ascribed to "aberrant" SHM. [12][13][14][15][16][17][18] Given the indications that SOCS1 is a target of SHM, SOCS1 inactivation by SHM could, in addition to HL and PMBL, also contribute to lymphomagenesis in other GC or post-GC B cellderived lymphomas. We thus analyzed the SOCS1 mutation status of other B-cell lymphomas, and, to clarify whether SOCS1 mutations are the result of (aberrant) SHM, also in normal GC and naive B cells, T-cell lymphomas, and solid tumors with constitutive activated STATs.…”

Section: Introductionmentioning

confidence: 99%

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Mottok

Renné

Seifert

et al. 2009

Blood

115

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IntroductionSTAT transcription factors are constitutively activated in several malignancies, often resulting from genomic alterations that deregulate STAT-activating kinases or interfere with termination of STAT signaling. 1,2 SOCS1, whose expression is induced by activated STATs, terminates JAK/STAT signaling by binding to and marking phosphorylated JAK for proteasomal degradation. 1,3 Function-impairing mutations in SOCS1 have recently been observed in primary mediastinal B-cell lymphoma (PMBL) and classic and nodular lymphocyte-predominant Hodgkin lymphoma (HL) and were associated with accumulation of several phosphorylated STATs. [4][5][6][7][8][9] Analysis of the mutation pattern of SOCS1 in nodular lymphocyte-predominant HL indicated a somatic hypermutation (SHM) origin. 7 The SHM process is largely restricted to rearranged immunoglobulin V-genes in germinal center (GC) B cells. 10 However, SHM occasionally also targets other genes. Rare BCL6 and FAS mutations present in GC but not naive B cells were ascribed as byproducts of "normal" SHM, 11,12 whereas mutations in PIM1, c-MYC, RHOH, and PAX5, present in several B-cell lymphomas but not in normal GC B cells, were ascribed to "aberrant" SHM. [12][13][14][15][16][17][18] Given the indications that SOCS1 is a target of SHM, SOCS1 inactivation by SHM could, in addition to HL and PMBL, also contribute to lymphomagenesis in other GC or post-GC B cellderived lymphomas. We thus analyzed the SOCS1 mutation status of other B-cell lymphomas, and, to clarify whether SOCS1 mutations are the result of (aberrant) SHM, also in normal GC and naive B cells, T-cell lymphomas, and solid tumors with constitutive activated STATs. Methods Tissue samplesTissue samples were from the files of the Senckenberg Institute of Pathology and originally submitted for diagnostic purposes. Approval for this study was obtained from the University of Frankfurt School of Medicine Institutional Review Board. Informed consent was obtained in accordance with the Declaration of Helsinki. Isolation of single tonsillar GC and naive B cellsSingle GC and naive tonsillar B cells were sorted by fluorescence-activated cell sorter as CD20 ϩ CD38 intermediate IgD Ϫ and IgD ϩ CD23 ϩ CD27 Ϫ CD38 Ϫ cells, respectively, in 10 L of 1ϫ polymerase chain reaction (PCR) buffer (supplemental data, available on the Blood website; see the Supplemental Materials link at the top of the online article). Sequence analysis of SOCS1 and V gene rearrangementsGenomic DNA was extracted from sections of frozen samples and various cell lines. DNA (10-100 ng) was used as template for amplification of the complete open reading frame of SOCS1 in a single-round PCR. PCR products were purified and directly sequenced. In cases with several mutations, genomic DNA was diluted and aliquots of various dilutions were amplified in a 2-round nested PCR. PCR products obtained from dilutions For personal use only. on May 11, 2018. by guest www.bloodjournal.org From where 30% to 50% of PCRs yielded PCR products were directly sequenced. For ampl...

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Somatic hypermutation of IGVH genes and aberrant somatic hypermutation in follicular lymphoma without BCL-2 gene rearrangement and expression

Cited by 23 publications

References 29 publications

In non‐follicular lymphoproliferative disorders, IGH/BCL2‐fusion is not restricted to chronic lymphocytic leukaemia

In non‐follicular lymphoproliferative disorders, IGH/BCL2‐fusion is not restricted to chronic lymphocytic leukaemia

MicroRNA profiles of t(14;18)–negative follicular lymphoma support a late germinal center B-cell phenotype

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

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