t(11;18)(q21;q21) is the most common translocation in MALT lymphomas

Background: Low grade malignant lymphomas arising from mucosa associated lymphoid tissue (MALT) represent a distinct clinicopathological entity. The cytogenetic findings and molecular genetics of MALT lymphomas remain minimally defined. Cytogenetic studies infrequently constitute part of the diagnostic work-up of MALT lymphomas, most commonly due to small biopsy size and their extranodal localization. Only 28 MALT cases with a clonal karyotype have been published to date. A number of chromosomal abnormalities have been observed with the majority of the cases featuring trisomy of chromosome 3 which is present in up to 78% of the cases.Materials and methods: A total of 116 cases of MALT lymphoma were diagnosed at BCCA between 1988 and 1997. Eleven cases of pathologically confirmed MALT lymphomas were subjected to cytogenetic analysis at the time of the initial evaluation. Eight of 11 cases yielded successful cultures and the presence of a clonal karyotype using standard cytogenetic methodology. In addition, a single case of orbital MALT lymphoma with a clonal karyotype has been obtained through our consultative practice from University of Nebraska Medical Center. These nine cases of MALT lymphoma with a clonal karyotype are the subject of this report.Results and conclusion: In this study we report nine cytogenetically studied MALT lymphomas, three of which feature a novel t(11;18)(q21;q21) translocation which has also been observed in five other MALT cases described in the literature. This recurrent translocation is the most common translocation associated with MALT lymphomas being present in 33% (three of nine) of our cases and 18% (five of 28) of the previously published cases. The results suggest that a potentially important gene located at one of these breakpoints may be involved in the pathogenesis of MALT lymphomas.     

Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas.

The recently discovered MLT/MALT1 gene is fused with the API2 gene in the t(11;18)(q21;q21), which characterizes about one-third of MALT lymphomas. In order to screen for variant translocations and amplifications of MLT/MALT1, we have developed a novel, undirected two-color interphase fluorescence in situ hybridization (FISH) assay with two PAC clones flanking MLT/MALT1. This assay was applied to 108 marginal zone B-cell lymphomas (MZBCLs), including 72 extranodal MALT lymphomas, 17 nodal, and 19 splenic MZBCL. In 19 MALT lymphomas (26%), but in none of the nodal or splenic MZBCL, separated hybridization signals of the MLT/MALT1 flanking probes, were found. Further FISH analyses showed that 12 of these 19 cases displayed the classical t(11;18) and the remaining seven cases revealed the novel t(14;18)(q32;q21), involving the MLT/MALT1 and IGH genes. The frequency at which these translocations occurred varied significantly with the primary location of disease. The t(11;18) was mainly detected in gastrointestinal MALT lymphomas, whereas the t(14;18) occurred in MALT lymphomas of the parotid gland and the conjunctiva. Amplification of MLT/MALT1 was not observed in any of the lymphomas analyzed. We conclude that the translocations t(11;18)(q21;q21) and t(14;18)(q21;q32) represent the main structural aberrations involving MLT/MALT1 in MALT lymphomas, whereas true amplifications of MLT/MALT1 occur rarely in MZBCL.     

Helicobacter pylori and the t(11;18)(q21;q21) translocation in gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type.

The reported regression of mucosa-associated lymphoid tissue (MALT) type gastric low-grade B-cell lymphoma following treatment for Helicobacter pylori (H. pylori) infection has not yet been comprehensively analyzed, especially in relation to the recently identified c-IAP2-MALT1 / MLT gene alteration resulting from the t(11;18)(q21;q21) chromosomal translocation found in MALT lymphoma. The relationship between MALT lymphomas and H. pylori was investigated in 30 patients who received an antibacterial treatment. Patients were followed up by means of endoscopy and biopsy. Molecular genetic analyses focused on the presence or absence of the immunoglobulin heavy chain (IgH) gene and / or MALT1 / MLT gene alteration resulting from t(11;18)(q21;q21) translocation. H. pylori was positive in 26 of the 30 patients. The overall success rate of cure of H. pylori infection was 96% (25 / 26). Thirteen patients (52%) showed complete remission (CR) of lymphoma, nine (36%) partial remission (PR), and three (12%) registered no change (NC). Statistical analysis revealed significant differences between CR and PR / NC patients in age ( < 60 or 60), in lymphoma location (single or multiple sites) and in the presence or absence of gene rearrangement before eradication (P < 0.05). Endoscopy showed a cobblestone appearance only in PR cases and polypoid features predominantly in NC cases. Two NC patients with polypoid gross appearance showed rearrangements involving either c-IAP2 or MALT1 gene in Southern blot analysis, while none of seven other resected patients with non-polypoid superficial gross appearance showed rearrangement. Gastric MALT lymphoma could be pragmatically subdivided into three groups, CR (MALT-A), PR (MALT-B), and NC (MALT-C) on the basis of the reaction to eradication of H. pylori. We speculate that MALT-A may represent an incipient neoplasm or dysplasia, MALT-B a neoplasm activated by antigenic stimulation of H. pylori, and MALT-C a lymphoma independent of H. pylori. Polypoid lesions in MALT-C were associated with c-IAP2-MALT1 / MLT gene alteration resulting from t(11;18)(q21;q21). This classification is thought to be clinically significant for deciding the most appropriate mode of treatment of MALT-type lymphoproliferative disorders.     

Helicobacter pylori and the t(11;18)(q21;q21) Translocation in Gastric Low-grade B-Cell Lymphoma of Mucosa-associated Lymphoid Tissue Type

The reported regression of mucosa‐associated lymphoid tissue (MALT) type gastric low‐grade Bcell lymphoma following treatment for Helicobacter pylori (H. pylori) infection has not yet been comprehensively analyzed, especially in relation to the recently identified c‐IAP2‐MALT1/MLT gene alteration resulting from the t(11;18)(q21;q21) chromosomal translocation found in MALT lymphoma. The relationship between MALT lymphomas and H. pylori was investigated in 30 patients who received an antibacterial treatment. Patients were followed up by means of endoscopy and biopsy. Molecular genetic analyses focused on the presence or absence of the immunoglobulin heavy chain (IgH) gene and/or MALT1/MLT gene alteration resulting from t(11;18)(q21;q21) translocation. H. pylori was positive in 26 of the 30 patients. The overall success rate of cure of H. pylori infection was 96% (25/26). Thirteen patients (52%) showed complete remission (CR) of lymphoma, nine (36%) partial remission (PR), and three (12%) registered no change (NC). Statistical analysis revealed significant differences between CR and PR/NC patients in age (< 60 or 60), in lymphoma location (single or multiple sites) and in the presence or absence of gene rearrangement before eradication (P< 0.05). Endoscopy showed a cobblestone appearance only in PR cases and polypoid features predominantly in NC cases. Two NC patients with polypoid gross appearance showed rearrangements involving either c‐IAP2 or MALT1 gene in Southern blot analysis, while none of seven other resected patients with non‐polypoid superficial gross appearance showed rearrangement. Gastric MALT lymphoma could be pragmatically subdivided into three groups, CR (MALT‐A), PR (MALT‐B), and NC (MALT‐C) on the basis of the reaction to eradication of H.pylori. We speculate that MALT‐A may represent an incipient neoplasm or dysplasia, MALT‐B a neoplasm activated by antigenic stimulation of H. pylori, and MALT‐C a lymphoma independent of H. pylori. Polypoid lesions in MALT‐C were associated with c‐IAP2‐MALT1/MLT gene alteration resulting from t(11;18)(q21;q21). This classification is thought to be clinically significant for deciding the most appropriate mode of treatment of MALT‐type lymphoproliferative disorders.     

t(11;18)(q21;q21) translocation as predictive marker for non-responsiveness to salvage thalidomide therapy in patients with marginal zone B-cell lymphoma with gastric involvement

Purpose  

Activation of TNF-α/NF-κB-related signaling pathway is crucial in sustain the growth of Helicobacter pylori-independent gastric mucosa-associated lymphoid tissue type (MALT) lymphoma. Thalidomide is an anti-angiogenic agent with anti-TNF-α and anti-NF-κB activity. This retrospective study evaluated the efficacy of thalidomide in standard therapy-failure gastric MALT lymphoma.     

Correlation of secondary cytogenetic abnormalities with histologic appearance in non-Hodgkin's lymphomas bearing t(14;18)(q32;q21)

Successful cytogenetic studies were performed on 69 biopsies from 64 patients with non-Hodgkin's lymphoma bearing a t(14;18)(q32;q21) translocation. This translocation appears to be a primary abnormality associated with the development of certain B-cell non-Hodgkin's lymphomas. We correlated the occurrence of secondary abnormalities, in addition to the t(14;18)(q32;q21), with histologic subtype to test the hypothesis that secondary abnormalities correlate with more aggressive histologic appearance. A large number of secondary abnormalities were identified, the most frequent being additional copies of chromosomes 7 (30%), 12 (22%), 18 (22%), 20 (16%), or 21 (14%), deletion of a portion of the long arm of chromosome 6 (17%), and either an additional chromosome 17 or an isochromosome for the long arm of chromosome 17 (13%). An extra chromosome 7 was highly associated with a diffuse histologic pattern; it was present in 52% of patients with a diffuse pattern and in only 15% of those with a follicular pattern (P = .002). A weaker association with a diffuse growth pattern was found for the addition of chromosome 17 or an i(17q); it was found in 24% of patients with a diffuse pattern and only 5% of those with a follicular pattern (P = .05). No other significant correlations between secondary chromosome abnormalities and histologic subtype were identified. Although the explanation for this association is not clear, it appears that patients with B-cell non-Hodgkin's lymphomas bearing the t(14;18)(q32;q21) translocation which also have an additional chromosome 7 are likely to exhibit a diffuse growth pattern.     

B-cell lymphoma possessing t(14;18)(q32;q21)in a patient with rheumatoid arthritis receiving methotrexate treatment

There is evidence of a slight increase in malignant lymphoma among rheumatoid arthritis(RA)patients receiving methotrexate( MTX). Increased rates of lymphoma have been attributed to reactivation of the Epstein-Barr virus(EBV). A 72-yearold woman was admitted to our hospital for generalized lymph adenopathy. She suffered from RA and has been treated with MTX for 7 years; the total amount of MTX received was around 2, 700 mg. The cervical lymph node revealed a diffuse proliferation of large atypical lymphocytes. An immunophenotype revealed CD10+, CD19+, CD20+, and k+. The chromosome analysis showed a complex abnormality containing t(14;18)(q32;q21). The tumor cells were positive for EBV sequences by in situ hybridization(ISH). A rituximab containing regimen was effective, but a systemic relapse occurred 4 years later. The biopsied sample was diagnosed as diffuse large B-cell lymphoma. FISH analysis revealed positive for t(14;18)(q32;q21), however, EBV was negative using ISH. In general, the concurrence of t(14;18)(q32;q21)and EBV in the B-cell lymphoma is rare. In addition, the negative change in EBV in the relapsed lymphoma cells revealed a quite rare phenomenon.     

A new non-Hodgkin's B-cell line (DoHH2) with a chromosomal translocation t(14;18)(q32;q21).

A spontaneously growing EBV-negative B-cell line (DoHH2) was established from the pleural fluid cells of a 60-year-old man with centroblastic/centrocytic non-Hodgkin's lymphoma, that had transformed into an immunoblastic lymphoma. The pleural fluid cells and the DoHH2 cells expressed IgG lambda, were reactive with CD10 and CD19 monoclonal antibodies, and showed by cytogenetic analysis 48,XY, +7, +del(12)(q24), t(14;18)(q32;q21). Southern blot analysis of mini-satellite DNA patterns, and of rearrangements of the immunoglobulin genes and bcl-2, confirmed that the cell line was derived from the patient's clonal lymphoma cells. Direct nucleotide sequence analysis on polymerase chain reaction (PCR) products of the t(14;18) junction revealed an identical sequence for the JH-bcl-2 junction at JH6 and in the major breakpoint region of bcl-2 in both the original tumor cells and the DoHH2 cell line. The cell line was valuable as a standard quantification control for PCR analysis of the t(14;18) breakpoint. Titration experiments demonstrated the detection of up to one tumor cell in 10(5) normal blood lymphocytes.     

T(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the V(H) gene mutation status

AIM: To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker CD27. METHODS: The VH gene of 7 t(11;18)(q21;q21)- positive gastrointestinal MALT lymphomas was amplif iedby PCR using family specif ic VH primers and a consensus JH primer. PCR products were sequenced and mutation analysis of the CDR and the FR regions was performed. All cases were immunostained for CD27. RESULTS: One case showed unmutated VH genes while the others showed mutated VH genes with mutation frequencies ranging from 1.3 to 14.7% and with evidence of antigen selection in 2 cases. These data suggest that the translocation t(11;18)(q21;q21) can target either B-cells at different stages of differentiation or naive B-cells that retain the capacity to differentiate upon antigen stimulation. All cases but one displayed weak to strong CD27 expression which did not correlate with the VH gene mutation status. CONCLUSION: t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the VH mutation status and CD27 is not a marker of somatically mutated B-cells.     

Translocation t(9;11)(p21;q23) in pediatric de novo and secondary acute myeloblastic leukemia.

The t(9;11)(p21;q23) has been associated with characteristic clinical features and a superior treatment outcome in previously untreated pediatric acute myeloblastic leukemia (AML), but has not been well studied in children with secondary AML. This translocation was detected in 6.7% of de novo and 46% of secondary AML patients treated at St Jude Children's Research Hospital over an 11-year period. Clinical, immunophenotypic, and morphologic characteristics were examined for the cases of t(9;11) secondary AML (n = 12) and compared with findings for children with t(9;11) de novo AML (n = 12). Patients with t(9;11) secondary AML were older at diagnosis, had higher hemoglobin levels, and central nervous system leukemia or hepatosplenomegaly was less frequent. These differences probably reflect survival of the first malignancy and close clinical scrutiny during post-treatment follow-up. Whereas the t(9;11)(p21;q23) occurred exclusively in the French-American-British (FAB) M5 subtype in de novo AML, the FAB M0 and M4 subtypes were also represented in secondary cases. The complete remission rate was somewhat higher for the de novo AML group (91 vs 58%; p = 0.16); their event-free survival was clearly superior to that for children with t(9;11) secondary AML (p = 0.003). Host differences related to the previous malignancy or its treatment could explain the poorer clinical outcome for patients with t(9;11) secondary AML. Alternatively, there could be critical differences at the translocation site or additional, hidden molecular events, that explain the different outcomes.     

Acute leukemias with the t(4;11)(q21;q23).

The t(4;11)(q21;q23) has been associated with marked lineage heterogeneity. Most of the reported cases were classified as acute lymphoblastic leukemia (ALL). The t(4;11) is one of the commonest specific chromosomal translocations in ALL, occurring in 2% of childhood and 5% of adult cases. In childhood ALL, this translocation is associated with female sex, age less than 1 year, hyperleukocytosis, CD10-/CD19+ B-precursor cell immunophenotype, and myeloid-associated antigen (CD15) expression. There also appears to be an age-related difference in treatment outcome. Adults had the worst prognosis, and children aged 1 to 9 years appeared to have a better outcome than infants or adolescents. Reported cases of acute myeloid leukemia (AML) or secondary leukemia with the t(4;11) have not been well characterized. It is intriguing that virtually all of the reported cases with secondary leukemia had received epipodophyllotoxins or doxorubicin, agents that affect topoisomerase II and are associated with secondary AML characterized by 11q23 abnormalities. Identification of the involved gene(s) in the t(4;11) will provide a molecular approach permitting more accurate classification of these cases.     

Translocation t(3;22)(q23;q11) in three patients with diffuse large B cell lymphoma

In our series of 134 patients with a diagnosis of non-Hodgkin's lymphoma (NHL) and clonal chromosomal abnormalities, three were found to show an identical t(3;22)(q28;q11) translocation. All were old patients with isolated lymphadenomegaly and diffuse large noncleaved cell lymphoma. All expressed a B cell immunophenotype, and all entered a complete remission when treated with aggressive chemotherapy. This translocation could, therefore, delineate a particular subtype of diffuse large cell NHL.     

Constitutive NF-kappaB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity

Mucosa-associated lymphoid tissue (MALT) lymphoma is a common type of lymphoma in extranodal sites. The most frequent chromosome translocation associated with MALT lymphoma is t(11;18)(q21;q21), which generates a chimeric protein of c-IAP2 and MALT1/paracaspase. The c-IAP2/MALT1 fusion protein activates the NF-kappaB pathway, which is considered critical to malignant B cell transformation and lymphoma progression. The mechanism by which this fusion protein activates NF-kappaB, however, remains unclear. Here we show that self-oligomerization of the c-IAP2/MALT1 protein causes deregulated ubiquitin ligase activity of MALT1/paracaspase. The chimeric protein targets NEMO for polyubiquitination and thereby activates NF-kappaB. Consistent with this finding, NEMO ubiquitination is increased in t(11;18)(q21;q21)-positive MALT lymphoma samples. Thus, t(11;18)(q21;q21) deregulates MALT1/paracaspase ubiquitin ligase activity, causing constitutive NF-kappaB activation and promoting tumorigenesis.     

Molecular characterization of a t(11;14)(q23;q32) chromosome translocation in a B-cell lymphoma

We have analyzed the molecular features of a t(11;14)(q23;q32) chromosome translocation of a cell line established from a B-cell lymphoma. Somatic hybrid cells carrying the 11q- and/or 14q+ chromosome(s) were produced in order to map the breakpoints. Southern blot analyses of DNAs from these hybrid cell lines together with various probes from the IGH locus on chromosome 14 and the ETS-1 and CD3 genes on chromosome 11 showed that the breakpoints of the translocation occurred between the constant regions of the C phi gamma and C gamma 2 genes on chromosome 14 and between the CD3 and ETS-1 genes on chromosome 11. The t(11;14)(q23;q32) translocation does not seem to involve the same mechanism that is responsible for translocations occurring at the immunoglobulin heavy chain joining segment (JH).     

Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations.

Chromosomal region 11q23 participates in a number of reciprocal translocations with specific regions of chromosomes 4, 9, 19, and others. These translocations are associated with acute lymphocytic leukemia and acute myelomonocytic, monocytic, and myelogenous leukemia. From a yeast artificial chromosome containing human DNA derived from 11q23 we cloned a DNA fragment which can be used as a probe to detect rearrangements in leukemic cells from the majority of patients with the t(4;11), t(9;11), and t(11;19) translocations. The breakpoints cluster in a small DNA region of less than 5.8 kilobases.