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.     

Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18

Lymphomas arising in mucosa-associated lymphoid tissue (MALT) are indolent B-cell tumors that have a predilection for epithelial sites and often develop in a setting of chronic inflammation or autoimmunity. As many as 50% of low-grade MALT lymphomas contain an (11;18)(q21; q21) chromosomal translocation. Using fluorescence in situ hybridization, we have analyzed the position of recombination within chromosome 18 DNA in three examples of MALT lymphoma bearing this translocation. In all three cases, the breakpoint maps to DNA in BAC b357H2, covering about 150 kb of sequence. A previously undescribed, ubiquitously expressed gene, which we refer to as MALT1, was identified within this sequence and was found to be broken in one case for which we have definitively located the position of recombination between chromosomes 18 and 11. The sequence of this gene indicates the presence of two immunoglobulin-like C2 domains and a region of partial homology to caspases, suggesting a possible role for MALT1 in the regulation of apoptosis.     

Stability and subcellular localization of API2-MALT1 chimeric protein involved in t(11;18) (q21;q21) MALT lymphoma

t(11; 18) (q21; q21) is a chromosomal aberration specific to low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and generates the chimeric product apoptosis inhibitor 2 (API2)-MALT1, which has been suggested to play an important role in MALT lymphomagenesis. However, little is known about the characteristics of API2, MALT1, and API2-MALT1 proteins. We therefore investigated the subcellular localization and stability of these products. API2 was localized in the nucleus and the cytoplasm, and MALT1 and API2-MALT1 in the cytoplasm only. Western blot analysis showed that the products of API2 and MALT1 were unstable, while the API2-MALT1 product was stable. The API2 deletion mutants at the end of the C-terminal and the MALT1 deletion mutants at the end of the N-terminal were stable compared with the full-length products. These results indicate that the domains responsible for protein instability are located in the end of the C-terminal of API2 and in that of the N-terminal of MALT1, and also that API2-MALT1 became stable because it lacks these domains. It has been suggested that NF-kappaB activation plays an important role in the tumorigenesis of MALT lymphoma. Our findings further suggest that the stabilized expression of API2-MALT1 products may continuously stimulate the NF-kappaB activating pathway, thus leading to MALT lymphomagenesis.     

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.     

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.     

Novel insights into the mechanism of t(14;18)(q32;q21) translocation in follicular lymphoma

The t(14:18)(q32:q21) chromosomal translocation and the ensuing overexpression of the BCL-2 proto-oncogene are strongly associated with the pathogenesis of follicular lymphoma. At the molecular level, the translocation process arises from the illegitimate rearrangement between the BCL-2 proto-oncogene and the immunoglobulin heavy chain (IgH) locus. Due to the presence of the D(H) and J(H) gene segments from the IgH locus as well as de novo nucleotide additions at the breakpoints, the translocation process has been assumed to result from a mistake occurring during V(D)J recombination in early B-cells in the bone marrow. However, recent detailed molecular analyses of both the direct and reciprocal breakpoints have revealed that the t(14;18) translocation is a more complex process than previously thought, and have challenged this traditional view. Here we review these observations, and discuss the intriguing possibility that t(14;18) translocation could preferentially occur in the germinal centers during receptor revision, and involves both V(D)J recombination and somatic hypermutation mechanisms.     

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.     

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.     

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.     

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.     

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.     

Pediatric leukemia/lymphoma with t(8;14)(q24;q11).

A variety of chromosomal translocations occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL) in which a cellular oncogene or growth-related gene is translocated to the alpha/delta locus of the T-cell receptor gene. The t(8;14)(q24;q11) has been described at the cytogenetic and molecular level, but the disease associated with this translocation has not been defined clinically. Fifteen pediatric cases of leukemia/lymphoma with a t(8;14)(q24;q11) chromosomal translocation were collected from previous publications and institutional records. The estimated prevalence of this abnormality among all cases of ALL was 1%. The t(8;14)(q24;q11) disease was characterized by male predominance (10/15), a median age of 5.5 years (range 1.8-17 years), high white blood cell count (median 95 x 10(9)/l), central nervous system infiltration (4/11), bulky extramedullary leukemia (10/11), and T-cell immunophenotype (12/15). The median event-free survival was 4 months, and the median survival, 11 months. Seven cell lines with t(8;14)(q24;q11) were established from six of the cases; four were T-lymphoblastic, one was T-lymphoblastic, but expressed myeloid-related antigens, and two were predominantly myeloid. t(8;14)(q24;q11) leukemia/lymphoma and other ALLs involving 13(q11) have in common a high tumor burden, early spread to extramedullary sites, a propensity to form T-lymphoblastic or T-myeloid cell lines and, usually, an aggressive clinical course.     

The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21)

The MLL gene at chromosome 11q23 is frequently rearranged in acute leukemia. Here we report the identification of a new MLL fusion partner in the case of an infant with AML-M4 and a t(11;17)(q23;q21) translocation. Fluorescence in situ hybridization (FISH) and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 or MSF. Rapid amplification of cDNA ends (RACE) revealed an in-frame fusion of MLL to LASP1, a gene that is amplified and overexpressed in breast cancer. Retroviral transduction of myeloid progenitors demonstrated that MLL/LASP1 is the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, thus establishing a potential subgroup among the MLL fusion proteins.