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Alexandra Traverse-Glehen,
Emmanuel Bachy,
Lucile Baseggio,
Evelyne Callet-Bauchu, Sophie Gazzo,
Aurélie Verney,
Sandrine Hayette,
Laurent Jallades,
Martine Ffrench,
Gilles Salles,
Bertrand Coiffier,
Pascale Felman,
Francoise Berger
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ABSTRACT: To describe 76 cases of splenic marginal zone lymphoma (SMZL), including correlations with clinical and other characteristics.
Patients were predominantly female, with a median age of 62 years. The main clinical presentation was splenomegaly, except for eight cases presenting with evolution of autoimmune disorders or spontaneous splenic rupture. White pulp infiltration was nodular, with a monophasic (42%) or biphasic (53%) pattern, and associated diffuse or nodular infiltration of the red pulp, except for four cases which had atrophic white pulp. Plasmacytic differentiation and the MYD88 L265P mutation were observed in 18% and 5% of the cases, respectively. Histological progression was considered in cases with a significant association of large cells with Ki67 > 30% and macronodular architecture (P = 0.001). Other significant correlations were found between del7q (44%) and del6q (17%) (P = 0.018), IGHV1-2*04 segment usage (35%) (P = 0.001) and unmutated IGHV (39%) (P = 0.019), and between CD5 expression (27%) and higher lymphocytosis (P = 0.002). Patients requiring intensive chemotherapy after splenectomy because of clinical and/or histological progression had significantly shorter overall survival (P = 0.012).
We report the histological spectrum of SMZL, and discuss the differential diagnosis and requirement for molecular and cytogenetic analysis in atypical cases.
Histopathology 05/2013; 62(6):876-93. · 3.08 Impact Factor
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Lucile Baseggio,
Marie-Odile Geay, Sophie Gazzo,
Françoise Berger,
Alexandra Traverse-Glehen,
Martine Ffrench,
Sandrine Hayette,
Evelyne Callet-Bauchu,
Aurélie Verney,
Dominique Morel,
Laurent Jallades,
Jean-Pierre Magaud,
Gilles Salles,
Pascale Felman
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ABSTRACT: The 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.
British Journal of Haematology 06/2012; 158(4):489-98. · 4.94 Impact Factor
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Sandrine Hayette,
Xavier Thomas,
Laurent Jallades,
Kaddour Chabane,
Carole Charlot,
Isabelle Tigaud, Sophie Gazzo,
Stéphane Morisset,
Pascale Cornillet-Lefebvre,
Adriana Plesa,
Sarah Huet,
Aline Renneville,
Gilles Salles,
Franck Emmanuel Nicolini,
Jean-Pierre Magaud,
Mauricette Michallet
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ABSTRACT: It has been recently shown that DNA methyl transferase overexpression is correlated with unfavourable prognosis in human malignancies while methylation deregulation remains a hallmark that defines acute myeloid leukemia (AML). The oncogenic transcription factor EVI1 is involved in methylation deregulation and its overexpression plays a major role for predicting an adverse outcome. Moreover, the identification of DNMT3A mutations in AML patients has recently been described as a poor prognostic indicator. In order to clarify relationship between these key actors in methylation mechanisms and their potential impact on patient outcomes, we analysed 195 de novo AML patients for the expression of DNMT3A, 3B (and its non-catalytic variant 3B(NC)) and their correlations with the outcome and the expression of other common prognostic genetic biomarkers (EVI1, NPM1, FLT3ITD/TKD and MLL) in adult AML. The overexpression of DNMT3B/3B(NC) is (i) significantly correlated with a shorter overall survival, and (ii) inversely significantly correlated with event-free survival and DNMT3A expression level. Moreover, multivariate analysis showed that a high expression level of DNMT3B/3B(NC) is statistically a significant independent poor prognostic indicator. This study represents the first report showing that the overexpression of DNMT3B/3B(NC) is an independent predictor of poor survival in AML. Its quantification should be implemented to the genetic profile used to stratify patients for therapeutical strategies and should be useful to identify patients who may benefit from therapy based on demethylating agents.
PLoS ONE 01/2012; 7(12):e51527. · 4.09 Impact Factor
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Eva Maria Murga Penas,
Evelyne Callet-Bauchu,
Hongtao Ye, Sophie Gazzo,
Françoise Berger,
Georgia Schilling,
Nadine Albert-Konetzny,
Eik Vettorazzi,
Gilles Salles,
Iwona Wlodarska,
Ming-Qing Du,
Carsten Bokemeyer,
Judith Dierlamm
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ABSTRACT: The t(14;18)(q32;q21) involving the immunoglobulin heavy chain locus (IGH) and the MALT1 gene is a recurrent abnormality in mucosa-associated lymphoid tissue (MALT) lymphomas. However, the nucleotide sequence of only one t(14;18)-positive MALT lymphoma has been reported so far. We here report the molecular characterization of the IGH-MALT1 fusion products in 5 new cases of t(14;18)-positive MALT lymphomas. Similar to the IGH-associated translocations in follicular and mantle cell lymphomas, the IGH-MALT1 junctions in MALT lymphoma showed all features of a recombination signal sequence-guided V(D)J-mediated translocation at the IGH locus. Furthermore, analogous to follicular and mantle cell lymphoma, templated nucleotides (T-nucleotides) were identified at the t(14;18)/IGH-MALT1 breakpoint junctions. On chromosome 18, we identified a novel major breakpoint region in MALT1 upstream of its coding region. Moreover, the presence of duplications of MALT1 nucleotides in one case suggests an underlying staggered DNA-break process not consistent with V(D)J-mediated recombination. The molecular characteristics of the t(14;18)/IGH-MALT1 resemble those found in the t(14;18)/IGH-BCL2 in follicular lymphoma and t(11;14)/CCND1-IGH in mantle cell lymphoma, suggesting that these translocations could be generated by common pathomechanisms involving illegitimate V(D)J-mediated recombination on IGH as well as new synthesis of T-nucleotides and nonhomologous end joining (NHEJ) or alternative NHEJ repair pathways on the IGH-translocation partner.
Blood 11/2009; 115(11):2214-9. · 9.90 Impact Factor
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Alexandre Ottaviani,
Caroline Schluth-Bolard,
Sylvie Rival-Gervier,
Amina Boussouar,
Delphine Rondier,
Andrea M Foerster,
Julia Morere,
Serge Bauwens, Sophie Gazzo,
Evelyne Callet-Bauchu,
Eric Gilson,
Frédérique Magdinier
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ABSTRACT: The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome.
The EMBO Journal 08/2009; 28(16):2428-36. · 9.20 Impact Factor
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Catherine Thieblemont,
Delphine Rolland,
Lucile Baseggio,
Pascale Felman, Sophie Gazzo,
Evelyne Callet-Bauchu,
Alexandra Traverse-Glehen,
Rémi Houlgatte,
Kai Fu,
Dennis Weisenburger,
Daphne De Jong,
Elaine S Jaffe,
Andreas Rosenwald,
German Ott,
Bertrand Coiffier,
Françoise Berger
Leukemia & lymphoma 08/2008; 49(7):1403-6. · 2.40 Impact Factor
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Alexandra Traverse-Glehen,
Lucile Baseggio,
Evelyne Callet- Bauchu,
Dominique Morel, Sophie Gazzo,
Martine Ffrench,
Aurélie Verney,
Delphine Rolland,
Catherine Thieblemont,
Jean-Pierre Magaud,
Gilles Salles,
Bertrand Coiffier,
Françoise Berger,
Pascale Felman
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ABSTRACT: The presence of circulating villous lymphocytes (VLs) in lymphoma patients usually points to splenic marginal zone B-cell lymphoma (SMZL), even if the VLs can be found occasionally in other small B-cell lymphomas. However, those cells are variably described, and detailed cytologic characterization is often lacking. We identified lymphoma cases with numerous basophilic VLs among the large group of splenic lymphoma with VLs, and for further delineation, 37 cases with this particular cytology were analyzed. Patients, predominantly older men, presented with moderate lymphocytosis and splenomegaly without pancytopenia. The monoclonal B cells expressed IgM + D, IgM + G, IgM or IgG, as well as CD76 and CD11c, frequently CD103, and rarely CD123. Spleen sections were peculiar, with atrophic white pulp and a monomorphic diffuse lymphoma infiltration in a congested red pulp. Bone marrow infiltration was interstitial and intrasinusoidal without extensive fibrosis. Cytogenetic analysis showed a frequent absence of clonal aberrations (68%). Most cases (79%) were IgH mutated, with an overrepresentation of V(H)3 and V(H)4 gene families. These results, as well as the clinical evolution, show that those lymphoma cases represent a homogeneous group distinct from SMZL and reminiscent of hairy cell leukemia variant, perhaps corresponding to a separate lymphoma entity.
Blood 03/2008; 111(4):2253-60. · 9.90 Impact Factor
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ABSTRACT: This report deals with a case of Sézary syndrome, a rare peripheral T-cell lymphoproliferative disorder, in which cytogenetic analysis performed during the disease transformation revealed the presence of a t(9;22) (q34;q11.2) translocation. Molecular analyses identified a new transcript, an e8a4 BCR-ABL fusion mRNA which could be responsible for the disease transformation.
Haematologica 10/2007; 92(9):1277-8. · 6.42 Impact Factor
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ABSTRACT: High-resolution multicolor banding (mBAND) analysis was applied to precisely fine-map the genomic extent of 7q deletions in a series of 26 marginal zone lymphoma patients displaying the abnormality on conventional karyotypes. Using this approach, the breakpoints and the extent of deletions revealed by conventional banding techniques had to be re-defined in 70% of cases. Although no common minimal region of deletion was delineated, mBAND demonstrated the involvement of the 7q32 region in more than 90% of cases. In addition, unsuspected translocations and intrachromosomal changes could be identified in four cases. Taken together, these data demonstrate that mBAND represents an alternative cytogenetic tool in the comprehensive analysis of chromosome aberrations in hematologic malignancies, allowing rapid screening and precise delineation of structural rearrangements of a defined chromosome. This also confirms the localization in the vicinity of band 7q32 of putative candidate gene(s) involved in the pathogenic development of the disease.
Cancer Genetics and Cytogenetics 07/2007; 175(2):159-65. · 1.39 Impact Factor
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Eva M Murga Penas,
Evelyne Callet-Bauchu,
Hongtao Ye,
Kristina Hinz,
Nadine Albert,
Christiane Copie-Bergman, Sophie Gazzo,
Françoise Berger,
Gilles Salles,
Carsten Bokemeyer,
Ming-Qing Du,
Judith Dierlamm
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ABSTRACT: So far, only one variant translocation of the t(11;18)(q21;q21), the t(11;12;18) (q21;q13;q21), has been reported. We herein describe two new variant translocations, the t(6;18;11)(q24;q21;q21) and the t(11;14;18)(q21;q32;q21), occurring in mucosa-associated lymphoid tissue (MALT) lymphomas. In both cases, fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) revealed the presence of an 5'API2-3'MALT1 fusion product, encoded on the derivative chromosome 11. Exon 7 of API2 was fused with exon 5 of MALT1 in the t(11;14;18) and with exon 8 of MALT1 in the t(6;18;11). FISH revealed the involvement of the immunoglobulin locus in the t(11;14;18). Rapid amplification of cDNA ends (RACE)-PCR to detect the involved partner gene on 6q showed exclusively wild-type API2 and MALT1 sequences.
Haematologica 04/2007; 92(3):405-9. · 6.42 Impact Factor
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British Journal of Haematology 10/2006; 134(5):452. · 4.94 Impact Factor
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ABSTRACT: Primary low-grade B-cell lymphomas of the skin are separated into marginal zone and follicle center lymphomas according to the recent World Health Organization-European Organization for Research and Treatment of Cancer classification, with distinct histologic and immunohistochemical profiles. Some cases remain difficult to distinguish. The degree of relationship with their extracutaneous counterparts is currently being investigated on clinical, histologic and molecular grounds. Cytogenetic analysis using fluorescence in situ hybridization was performed on 12 frozen samples of infiltrated skin that had been classified as marginal zone lymphoma (MZL). Chromosomal changes known to be recurrently observed in systemic MZL of the mucosa-associated lymphoid tissue type, and in follicular center lymphoma were analyzed. These included trisomy for chromosomes 3, 7, 12, and 18 as well as t(14;18) IGH/BCL2, t(14;18) IGH/MLT1, and t(11;18) API2/MLT1 translocations. Complementary molecular search of IGH/BCL2 rearrangement using a polymerase chain reaction technique and of API2/MLT1 mRNA expression by reverse transcriptase-polymerase chain reaction were performed. Two cases showed evidence of trisomy 3 at levels varying from 14% to 20% of the analyzed cells. No other chromosomal abnormalities were found with those techniques in the remaining cases. These results demonstrate that known recurrent chromosomal abnormalities rarely occur in primary cutaneous MZLs and suggest the possibility of a variety of initial oncogenic events leading to a common downstream pathway. These data also underline that fluorescence in situ analysis on routine skin punch biopsies represents a reliable tool for the detection of chromosomal changes, but requires consistent dermal infiltration.
American Journal of Dermatopathology 09/2006; 28(4):287-92. · 1.20 Impact Factor
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ABSTRACT: Eighteen cases of mantle cell lymphomas (MCL) with an atypical t(11;14) were studied using fluorescence in situ hybridization experiments (FISH). The atypical presentation was confirmed and unsuspected duplicated cases were identified in six patients. These data underline that FISH analysis must be be systematically performed in cases with an aberrant presentation to prevent a misdiagnosis.
Haematologica 01/2006; 90(12):1708-9. · 6.42 Impact Factor
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ABSTRACT: The immunological profile of lymphoproliferative disorders is usually conserved whatever the involved site, thus allowing a reliable diagnosis from peripheral blood analysis, especially in small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL). Here we present a case wherein the cytology and immunophenotype of blood specimen and bone marrow argue in favor of SLL/CLL with a typical Matutes score (5/5), whereas the cyto-histology and immunophenotype of spleen specimen led to the diagnosis of splenic marginal zone B-cell lymphoma (SMZL). Moreover genomic analysis showed that the splenic cells displayed a SMZL signature. Whereas these data suggested the presence of 2 B-cell clones, the study of the mutational status of IgVH gene in blood and spleen demonstrated the presence of a single clone, which likely developed simultaneously along two distinct ways of differentiation according to the anatomic site suggesting here the predominant role of a micro-environmental factor in cell differentiation. Although rare, this kind of event must be kept in mind as a cause of discrepancies between diagnoses from different sites.
Leukemia and Lymphoma 10/2005; 46(9):1369-74. · 2.58 Impact Factor
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Alexandra Traverse-Glehen,
Frédéric Davi,
Elsa Ben Simon,
Evelyne Callet-Bauchu,
Pascale Felman,
Lucile Baseggio, Sophie Gazzo,
Catherine Thieblemont,
Carole Charlot,
Bertrand Coiffier,
Françoise Berger,
Gilles Salles
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ABSTRACT: To clarify the relationship between splenic (SMZL) and nodal marginal zone (NMZL) lymphomas, we analyzed immunoglobulin variable heavy chain (VH) gene usage and mutation patterns in these tumors.
VH genes were cloned and sequenced from 49 lymphoma samples (35 SMZL and 14 NMZL).
A biased usage of VH gene was found with overrepresentation of VH1 in SMZL cases (13/35) and VH4 in NMZL cases (7/14). Evidence for antigen driven mutations was identified in 8 SMZL and 4 NMZL cases. Three cases out of 18 with clones analyzed from spleen and peripheral blood demonstrated intra-clonal diversity, with evidence of clonal selection in one case, indicating the possibility of antigen-driven clonal expansion. Eleven SMZL cases (31%) but only 2 NMZL (14%) cases were unmutated. No differences in clinical outcome and overall survival were found between the unmutated and mutated cases.
The pattern of somatic mutation and the VH gene segment usage appear to differ between SMZL and NMZL, suggesting that these are distinct pathological entities. Moreover, a biased usage of certain sequences suggests that tumor cells in SMZL may be subjected to antigen selection.
Haematologica 05/2005; 90(4):470-8. · 6.42 Impact Factor
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Francoise Berger,
Alexandra Traverse-Glehen,
Pascale Felman,
Evelyne Callet-Bauchu,
Lucille Baseggio, Sophie Gazzo,
Catherine Thieblemont,
Martine Ffrench,
Jean Pierre Magaud,
Gilles Salles,
Bertrand Coiffer
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ABSTRACT: Waldenstrom's macroglobulinemia (WM) is considered in the World Health Organization classification as a clinical syndrome associated with monoclonal immunoglobulin (Ig) M secretion, mainly observed in patients with lymphoplasmacytic lymphoma (LPL) and occasionally with other small B-cell lymphomas. Some authors consider it a rare distinct lymphoproliferative disorder with primary bone marrow infiltration and IgM monoclonal gammopathy. As LPL shares important morphologic and immunophenotypic overlaps with marginal zone B-cell lymphomas (MZLs) in cases showing plasmacytic maturation, it remains unclear if they constitute unique or distinct entities. Both diseases are composed of lymphocytes, lymphoplasmacytoid cells, and tumoral plasma cells with a surface (s) IgM-positive sIgD+/ cytoplasmic IgMpositive CD19+ CD20+ CD27+/ CD5 CD10 CD23 phenotype, without a specific marker. Extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL (NMZL), and splenic MZL (SMZL) are distinct entities displaying common morphologic, immunophenotypic, and genetic characteristics. MALT lymphoma is clearly distinct from LPL, although bone marrow infiltration and IgM paraprotein are not rare. Splenic MZL and NMZL are incompletely characterized, but a plasmacytoid/plasmacytic differentiation, autoimmune manifestations, and monoclonal component are frequent in both diseases. Bone marrow involvement is constant in SMZL and present in 60% of NMZLs. Molecular IgVH gene analysis has confirmed this heterogeneity, particularly within SMZL, with mutated and unmutated cases. Further studies are needed to clarify the pathogenesis of these MZLs and their relationship with LPL.
Clinical lymphoma 04/2005; 5(4):220-4. · 3.11 Impact Factor
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Catherine Thieblemont,
Valéry Nasser,
Pascale Felman,
Karen Leroy, Sophie Gazzo,
Evelyne Callet-Bauchu,
Béatrice Loriod,
Samuel Granjeaud,
Philippe Gaulard,
Corinne Haioun, [......],
Lucile Baseggio,
François Bertucci,
Daniel Birnbaum,
Florence Magrangeas,
Stéphane Minvielle,
Hervé Avet-Loiseau,
Gilles Salles,
Bertrand Coiffier,
Françoise Berger,
Rémi Houlgatte
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ABSTRACT: Non-germinal center small B-cell lymphomas represent a heterogeneous group of non-Hodgkin lymphomas, the most frequent histologic subtypes being small lymphocytic lymphoma (SLL), splenic marginal zone B-cell lymphoma (MZL), and mantle cell lymphoma (MCL). In order to identify genomic signatures specific for each disease, we analyzed 128 primary tumors using high-density microarrays. Several clusters of genes significantly discriminated the 3 histologic subtypes. Genes associated with cell adhesion, angiogenesis, and inhibition of apoptosis were up-regulated in SLL. Genes associated with intracellular signaling via the AKT1 pathway were up-regulated in splenic MZL. Genes associated with cell cycle control and multidrug resistance were up-regulated in MCL. Using 44 genes selected within the gene clusters discriminant for the 3 lymphoma subtypes, we generated a class prediction score that allowed us to classify the 3 entities in 96% of the cases, including borderline cases. Whereas specific transcriptional profiles easily distinguished all MZL samples, SLL samples, and most of the MCL samples into separate groups, few MCL cases exhibited MZL-type transcriptional profiles. This study demonstrates that SLL, splenic MZL, and MCL possess specific transcriptional profiles that may be relevant to the pathogenesis and the diagnosis of these histologic subtypes.
Blood 05/2004; 103(7):2727-37. · 9.90 Impact Factor
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Sandrine Hayette,
Isabelle Tigaud,
Evelyne Callet-Bauchu,
Martine Ffrench, Sophie Gazzo,
Kamal Wahbi,
Mary Callanan,
Pascale Felman,
Charles Dumontet,
Jean-Pierre Magaud,
Ruth Rimokh
Blood 09/2003; 102(4):1549-50. · 9.90 Impact Factor
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ABSTRACT: Whole or partial trisomy 3 represents the most recurrent chromosomal abnormality occurring in marginal zone B-cell lymphoma (MZBCL), a distinct subtype of B-cell non-Hodgkin's lymphoma (NHL). By conventional cytogenetic analysis, unbalanced translocations involving chromosome 3 and leading to a partial trisomy 3q were identified in a series of 14 MZBCL patients. Fluorescent in situ hybridization (FISH) experiments were then performed to characterize the breakpoints further and to delineate the extent of the 3q gained region more accurately.
We studied 14 cases of MZBCL combining cytogenetics and FISH techniques using specific probes for the long arm of chromosome 3, including the chromosome 3 a satellite probe, a representative panel of yeast artificial chromosome (YAC) clones mapping the chromosomal 3q region (3q11.2 to 3q23) and the chromosome 3 subtelomeric (3q29) probe.
In the 14 cases, additional chromosome 3q material was found to be involved in different unbalanced translocations with chromosomes 1, 6, 7, 8, 11, 13, 14, 15, 17, 19 and 21, leading to a derivative chromosome. None of the chromosomal abnormality juxtaposed the 3q regions with the heavy and/or light k and l immunoglobulin gene loci. Eight different breakpoints distributed between the 3q11.2 and the 3q13.32 regions were identified and a common 3q13.32 3q29 overrepresented region was delineated.
These results suggest that this critical region may be of importance in the pathogenesis of MZBCL and support the hypothesis that a gene dosage effect rather than a specific gene disruption may be involved in the development of this disease.
Haematologica 02/2003; 88(1):31-8. · 6.42 Impact Factor
