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A Rosenwald

Publications and source records attributed to A Rosenwald.

At least 37 records · Page 2Linked to original sources
PubMed2000

Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.

Adult↗
PubMed2000

A 3-cM commonly deleted region in 6q21 in leukemias and lymphomas delineated by fluorescence in situ hybridization.

Deletions of the long arm of chromosome 6 (6q) are frequent chromosome aberrations in non-Hodgkin lymphomas (NHLs) and acute lymphoblastic leukemias (ALLs). It is presumed that one or more tumor suppressor genes are localized on 6q. By means of fluorescence in situ hybridization (FISH), we attempted to detect and delineate deletions of 6q in leukemias and lymphomas. We performed FISH on 148 cases of lymphoma and acute leukemia using a panel of 36 YAC probes distributed from 6q12 to 6q27 and a centromeric probe of chromosome 6 as internal control. Deletions of 6q that included a 7-cM commonly deleted region in 6q21 were detected in 59 patients who had B- and T-cell low-grade and high-grade NHL and ALL. FISH with two YAC probes flanking this region was performed on an additional 97 cases of NHL and leukemia. Deletions in 6q21 were detected in an additional 21 cases. In five cases of high-grade B- and T-cell NHL and ALL, the deletion breakpoints were located within the commonly deleted region. To define the deletion breakpoints exactly and to narrow this region further, FISH was performed with six additional YAC probes that have been physically localized within this region. A 3-cM (4-5 Mb) commonly deleted region in 6q21 was delineated. Our study suggests that this commonly deleted region harbors a putative tumor suppressor gene involved in the pathogenesis of both low-grade and high-grade NHL and ALL. Genes Chromosomes Cancer 27:52-58, 2000.

Chromosome Deletion↗
PubMed2000

Marginal zone B-cell lymphomas (MZBL) arising at different sites represent different biological entities.

Most entities of B-cell malignant non-Hodgkin's lymphomas (NHL) are characterized by typical primary chromosomal changes such as the t(14;18) in follicular lymphoma or the t(11;14) in mantle cell lymphoma. In contrast, marginal zone B-cell lymphomas (MZBL), arising at different nodal and extranodal sites, are poorly characterized on the genetic level. We performed cytogenetic investigations in 20 splenic and in 10 nodal MZBL and analyzed 52 MZBL (including 12 MALT-type lymphomas) for deletions of TP53, D13S25, and RB1 loci by fluorescence in situ hybridization. A new nonrandom chromosomal aberration, del(10)(q22q24), was found as a clonal anomaly in 3 out of 20 cases of splenic MZBL. Further recurring abnormalities such as del(7q) or trisomy 3 were found to be characteristic chromosomal changes in a subset of splenic MZBL. TP53 was deleted in 5/25 cases of splenic MZBL. Deletions involving band 13q14 were only rarely encountered, challenging a previous report that stated a dissociated D13S25-RB1 status as characteristic in splenic MZBL. There are fundamental differences between the different subtypes of marginal zone lymphomas as defined with current classification schemes. Splenic MZBL, in contrast to most other entities of B-cell NHL, seems to constitute a heterogeneous disease especially with regard to genetic alterations. del(10)(q22q24) could be of importance at least in a subset of this lymphoma entity.

Chromosome Aberrations↗
PubMed2000

Recurrent genetic aberrations in thymoma and thymic carcinoma.

Apart from single reported aberrant karyotypes, genetic alterations in thymic epithelial neoplasms have not been investigated so far. In this study, 12 World Health Organization classification type A thymomas (medullary thymomas), 16 type B3 thymomas (well-differentiated thymic carcinomas), and nine type C thymomas, all of them primary thymic squamous cell carcinomas, were analyzed by comparative genomic hybridization and fluorescence in situ hybridization. With the exception of one single case, type A thymomas did not reveal chromosomal gains or losses in comparative genomic hybridization. In contrast, all type B3 thymomas showed chromosomal imbalances, with gain of 1q, loss of chromosome 6, and loss of 13q occurring in 11 (69%), six (38%), and five (31%) of 16 cases, respectively. In primary thymic squamous cell carcinoma, the most frequent chromosomal losses were observed for 16q (six of nine cases, 67%), 6 (4 of 9, 44%), and 3p and 17p (three of nine each, 33%), whereas recurrent gains of chromosomal material were gains of 1q (5 of 9, 56%), 17q, and 18 (three of nine each, 33%). This study shows that the distinct histological thymoma types A and B3 exhibit distinct genetic phenotypes, whereas type B3 thymoma and primary thymic squamous cell carcinoma partially share genetic aberrations. In addition to the possible tumorigenic role, the deletion in type B3 thymoma of chromosome 6, harboring the HLA locus, might play a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma.

Adult↗
PubMed2000

Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma.

The translocation t(11;18)(q21;q21), which is the most frequent chromosomal aberration in extranodal marginal zone B cell lymphomas of MALT-type, was characterised in a series of 34 biopsies, including 18 gastric non-Hodgkin's lymphomas (NHL) of MALT-type, six MALT-type NHL of extragastral origin and 10 extranodal large B cell lymphomas (LBL). Based on fluorescence in situ hybridisation, STS-PCR analysis and screening of genomic PAC libraries, a physical map of contiguous DNA probes on chromosome 11 was constructed containing the anti-apoptotic genes API2 and API1 adjacent to the translocation breakpoint. RACE-PCR experiments revealed MALT1 the chromosome 18-derived fusion partner of API2, which has also been reported recently by other groups. RT-PCR analysis and DNA sequencing demonstrated the expression of an API2-MALT1 fusion transcript in 18/24 gastral and extragastral MALT-type lymphomas. In none of 10 LBLs was a translocation specific RT-PCR product detected. Five variants of the fusion transcript were identified and in all instances the open reading frame of the fused portion of the MALT1 gene was maintained. The molecular analysis of these variants allowed the design of optimised assays for the diagnosis of the API2-MALT1 gene rearrangement.

Caspases↗
PubMed2000

Genetic imbalances in primary gastric diffuse large B-cell lymphomas: comparison of comparative genomic hybridization, microsatellite, and cytogenetic analysis.

Extranodal malignant non-Hodgkin's lymphomas account for about 40% of lymphoid neoplasms, but few data are available concerning the genetic background of primary gastric diffuse large B-cell lymphoma (DLBCL). A study was performed of 27 primary gastric DLBCLs and 5 gastric DLBCLs with a concomitant low grade component of mucosa-associated lymphoid tissue-type lymphoma using comparative genomic hybridization (CGH), microsatellite studies, classic cytogenetics, and fluorescence in situ hybridization (FISH) to search for specific genetic aberrations. The most frequent aberrations were losses of material on chromosome 6q and gains of parts of chromosome 3. In three cases, a total of six high level DNA amplifications were detected, with five of them involving chromosomal regions not having been reported before in gastric DLBCL. A high overall concordance of 91.4% between microsatellite analysis and CGH was observed using DNA extracted from the same tissue block. The concordance achieved using DNA from different tissue blocks of the same patient was 85%. Microsatellite studies, CGH, FISH, and classic cytogenetics represent complementary techniques that facilitate a comprehensive view of genetic alterations in malignancies such as primary gastric DLBCL.

Adult↗
PubMed2000

[Genetic and biological features define two types of follicular non-Hodgkin grade 3 lymphoma].

In the REAL classification system, follicular lymphomas (FL) were subdivided into three grades depending on the number of blasts (6). In this study, we were interested in defining biological parameters possibly being important in the delineation of subgroups. Between 1990 and 1998, biological and cytogenetic investigations were performed on 91 FL. Clonal aberrations were found in all cases. The tumours were subclassified according to the blast content and the morphology of the centrocytes into 29 FL 1, 33 FL 2, 15 FL 3, and 14 FL 3 with a diffuse large B-cell lymphoma component (FL 3 + DLBL). They were characterised by classical cytogenetics, for their mitotic (MI) and proliferative (PI) indices, and CD10, bcl-2, and p53-expression. In contrast to FL 1 and FL 2, which showed a common genetic background with t(14;18), and only differed by their blast content and MI/PI, FL 3 (with or without associated DLBL) turned out to be an inhomogeneous group. 11 follicular lymphomas (with > 150 blasts/10HPF) still showed maturation to centrocytes. They were positive for CD10 and harboured the t(14;18) in 73%. These cases correspond to a "high grade" variant of centroblastic-centrocytic lymphoma according to the Kiel classification (FL 3a). In 18 cases with a follicular or follicular and diffuse growth pattern, the infiltrate consisted of centroblasts exclusively. These tumours were CD10+ in only 50% and were t(14;18)+ in only 22%. Secretory differentiation (clg+) was found in 44%. They were--with respect to primary and secondary chromosome aberrations--more comparable to a follicular variant of DLBL and hence, correspond to centroblastic lymphoma, follicular or centroblastic lymphoma, follicular and diffuse according to the Kiel classification (FL 3b). By histomorphological, biological and cytogenetic investigations, therefore, FL 3 can be delineated into two different biological subgroups with obviously different transformation pathways.

Antigens, CD↗
PubMed1999

TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.

Anaplastic large cell lymphoma (ALCL) is associated with the t(2;5)(p23;q35), which generates the NPM-ALK fusion gene encoding an 80-kD protein. Several studies have suggested that genes other than NPM may be fused to the ALK gene. Here we have identified TRK-fused gene (TFG) as a new ALK partner in 2 ALCL, 1 of which exhibited a t(2;3)(p23;q21). In these cases, TFG was involved in 2 different fusion genes, TFG-ALK(S) and TFG-ALK(L), coding respectively 85-kD and 97-kD chimeric proteins. The ALK breakpoint in these translocations was the same as in the classic t(2;5) translocation. These 2 proteins were both active in an in vitro tyrosine kinase assay showing that the new cloned cDNA sequences are translated into chimeric proteins with functional activity. These findings indicate that TFG can provide an alternative to NPM as a fusion partner responsible for activation of the ALK and the pathogenesis of ALCL.

Adult↗
PubMed1999

t(1;2)(q21;p23) and t(2;3)(p23;q21): two novel variant translocations of the t(2;5)(p23;q35) in anaplastic large cell lymphoma.

Cytogenetic investigations in two cases of anaplastic large cell lymphoma (ALCL) showed novel variants of the classical (2;5)(p23;q35) translocation, namely a t(1;2)(q21;p23) and a t(2;3)(p23;q21). The tumor cells in both cases gave positive immunohistochemical labeling for ALK protein (with both monoclonal and polyclonal antibodies), demonstrating that these translocations induce aberrant expression of this kinase and suggesting that genes other than NPM can activate the ALK gene in ALCL. These two cases were shown by an in vitro kinase assay to express ALK kinases (104 kD and 97 kD, respectively), which differed in size from the classical NPM-ALK fusion product (80 kD). Moreover, ALK expression was confined to the cytoplasm of the tumor cells in each case, supporting the hypothesis that the observed nuclear localization of NPM-ALK in classical ALCL is not the site of oncogenic activity of the ALK kinase.

Adolescent↗
PubMed1999

Jumping translocation of 1q as the sole aberration in a case of follicular lymphoma.

Cytogenetic and fluorescence in situ hybridization (FISH) studies in a case of follicular lymphoma grade III showed a "jumping translocation" of chromosome 1q21-qter to chromosomes Xq28 and 18q23, which resulted in a partial trisomy 1q as the only chromosome aberration. This case represents, to the best of our knowledge, the first report of a jumping translocation in a malignant lymphoma occurring as the sole aberration.

Chromosome Banding↗
PubMed1999

A biological role for deletions in chromosomal band 13q14 in mantle cell and peripheral t-cell lymphomas?

Structural aberrations of chromosomal band 13q14 are frequent in B-cell chronic lymphocytic leukemia (B-CLL) and target a putative tumor suppressor gene in the genomic region between the RB1 gene and the genetic marker D13S25. Recently, it has been suggested that alterations of this particular region might also be of relevance for the pathogenesis of mantle cell lymphomas (MCL). We applied dual-color fluorescence in situ hybridization (FISH) using probes for the RB1 and/or D13S25 loci and screened a total of 236 B- and T-cell non-Hodgkin's lymphomas (NHL) for deletions occurring in this genomic region. In MCL, the high rate (12/32; 38%) of hemizygous deletions and especially a deletion pattern similar to B-CLL in four of the cases provide further evidence that a substantial proportion of MCL cases may share a common way of pathogenesis with B-CLL. In other B-cell NHL, the frequency of allelic loss affecting 13q14 was overall low. However, the finding of 13q14 microdeletions in seven cases without detectable alterations of chromosome 13 at G-banding analysis might indicate a possible involvement of this genetic region also for the lymphomagenesis of single cases of B-cell NHL other than B-CLL and MCL. In T-cell NHL, allelic loss at 13q14 was encountered in three of 13 peripheral T-NHL, NOS. Taking into account the very limited cytogenetic data yet available in this entity, our series provides further evidence that 13q14 changes might represent one of the most frequent genetic abnormalities in T-cell NHL.

Chromosome Banding↗
PubMed1999

Biochemical detection of novel anaplastic lymphoma kinase proteins in tissue sections of anaplastic large cell lymphoma.

The (2;5) translocation, found in many T-cell and null cell anaplastic large cell lymphomas (ALCLs), creates a hybrid gene encoding the 80-kd NPM-ALK protein. Typically neoplastic cells show labeling of both nucleus and cytoplasm for anaplastic lymphoma kinase (ALK) and for the N-terminus of nucleophosmin (NPM). However, 10-20% of cases exhibit cytoplasmic labeling only for ALK, indicating the probable presence of variants of the classical (2;5) translocation that do not involve the NPM gene. We report the detection (using Western blotting and an in vitro kinase assay) in seven such ALCL cases, of ALK proteins with molecular masses of 85 kd, 97 kd (one case exhibiting a (2;3)(p23;q21) translocation), 104 kd (one case carried a (1;2)(q21;p23) translocation), and 113 kd. Tyrosine kinase activity was detected in four of these proteins, but the N-terminal portion of NPM could not be detected. These results show how ALCL cases that express ALK proteins other than NPM-ALK can be detected by sensitive biochemical techniques using routine cryostat sections.

Animals↗
PubMed1999

Exclusive detection of the t(11;18)(q21;q21) in extranodal marginal zone B cell lymphomas (MZBL) of MALT type in contrast to other MZBL and extranodal large B cell lymphomas.

Extranodal mucosa-associated lymphoid tissue (MALT)-type lymphomas and nodal and splenic marginal zone B cell lymphomas (MZBL) share morphological and immunophenotypic features with marginal zone B cells of reactive lymphoid tissues. Although displaying a similar immunophenotype, recent investigations suggest fundamental genetic differences among these subgroups. To determine the prevalence of the t(11;18) in a larger series of MALT-type lymphomas and to investigate a possible occurrence in other lymphomas, we screened 106 non-Hodgkin's lymphomas (NHL) by interphase cytogenetics using yeast artificial chromosome (YAC) probes flanking the breakpoint at 11q21. A signal constellation indicating a disruption in 11q21 and thus pointing to the presence of the t(11;18) was observed in 9 of 33 (27%) low-grade lymphomas of MALT type. The complete absence of t(11;18)-positive cells in 32 primary and secondary extranodal high-grade lymphomas suggests that low-grade lymphomas of MALT type characterized by the t(11;18) are unlikely to transform into high-grade tumors. The absence of tumor cells carrying the t(11;18) in nodal MZBL challenges the assumption that most, if not all, of these tumors represent the nodal manifestation of a so far undetected low-grade lymphoma of MALT type. The t(11;18) was not detected in a single case of 29 splenic MZBL investigated. This observation strengthens the view that splenic MZBL are biologically different from extranodal MZBL of MALT type.

Chromosome Banding↗
PubMed1999

Expression of costimulatory molecules in low-grade mucosa-associated lymphoid tissue-type lymphomas in vivo.

B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type develop against a background of chronic inflammation and have functional autoantigen receptors. Because they respond to environmental factors in vivo, the expression of costimulatory molecules, which play a key role in the differentiation of normal B-lymphocytes and in T-/B-cell interaction, may be critical in early MALT-type lymphoma pathogenesis until further chromosomal aberration leads to progression. We found a high number of tumor-infiltrating T-lymphocytes (TITLs) in all low-grade MALT-type lymphomas. The TITLs in low-grade lymphomas were activated and expressed a memory and immunocompetent phenotype. Reverse transcriptase-polymerase chain reaction analyses and immunohistochemistry confirmed the presence of CD40-ligand and Fas-ligand in 80% of low-grade lymphomas. In contrast to the TITLs, the tumor B cells did not express CD40-ligand or Fas-ligand in vivo or in vitro. Moreover, the cytokine profile in vivo suggested a Th2/Th3-weighted profile (interleukin-10, interleukin-13, transforming growth factor beta(1)) rather than Th1-weighted (interferon-gamma, interleukin-2). By interphase fluorescence in situ hybridization analysis the translocation t(11;18)(q21;q21) was found in four of nine (44%) cases studied. Interestingly, there was a four times higher proliferation and survival rate of purified t(11;18)-positive tumor B cells in vitro, although there were no significant profile differences from the TITLs in vivo. The finding of essential costimulating molecules in low-grade MALT-type lymphomas in vivo indicates a locally directed cognate T-/B-cell interaction. Consequently, a potentially equipped inflammatory background may not only determine the fate of autoreactive B-cells, but is also crucial to lymphoma maintenance and progression.

B-Lymphocyte Subsets↗
PubMed1998

Chromosomal abnormalities in nodal and extranodal CD30+ anaplastic large cell lymphomas: infrequent detection of the t(2;5) in extranodal lymphomas.

To determine the significance of the t(2;5)(p23;q35) translocation in nodal and extranodal anaplastic large cell lymphoma (ALCL), we performed cytogenetic, molecular genetic, and immunohistochemical analyses of tumor tissues from 11 patients with CD30+ ALCL. Three of five patients with nodal ALCL had additional infiltration of the skin. Six patients had extranodal ALCL, two had primary intestinal ALCL, three had a primary cutaneous ALCL, and one had osseous ALCL. Cytogenetic investigation detected the t(2;5) in all patients with nodal ALCL but not extranodal ALCL. Tumor cells in t(2;5)+ lesions also stained immunohistochemically for p80NPM/ALK, whereas no staining for p80NPM/ALK was detected in extranodal ALCL. Two extranodal lesions had NPM/ALK fusion transcripts detected by nested reverse transcriptase-polymerase chain reaction. Fluorescence in situ hybridization analysis of these two lymphomas showed in one case a significant number (4%) of cells with a split hybridization signal, indicative of disruption of the NPM gene. Additional recurrent breakpoints observed in extranodal ALCL were 1p36, 6p25, and 8q24. Loss of genetic material occurred at 6q in one extranodal ALCL. Our results suggest that the t(2;5) more frequently plays a pathogenetic role in primary nodal than in extranodal ALCL and that this translocation may not be the primary event in some CD30+ ALCL.

Adult↗
PubMed1998

Trisomy 3 is not a common feature in malignant lymphomas of mucosa-associated lymphoid tissue type.

The genetic background of extranodal marginal zone B-cell non-Hodgkin's lymphoma (NHL) of mucosa-associated lymphoid tissue (MALT) type is poorly understood. In contrast to most entities of primary nodal lymphomas, few cytogenetic data are available, and gene rearrangements frequently encountered in and highly characteristic of certain entities of systemic NHL are absent in this type of lymphoma. Recently, it was suggested that MALT-type NHLs are associated with certain numerical chromosome aberrations and especially with trisomy 3. We performed an extensive study using a sensitive double (bicolor) fluorescence in situ hybridization technique for the analysis of trisomies for chromosomes 3, 7, 12, and 18 in 60 samples of low-grade and 45 high-grade MALT-type tumors. In the low-grade cases, trisomy 3 was found in a frequency of only 20%. High-grade lymphomas of MALT type were associated with trisomies 3, 7, 12, and 18 in 36, 20, 18, and 13% of the cases, respectively. Whereas no difference was encountered for trisomy 3 in primary and secondary/simultaneous high-grade lymphomas, +7 and +12 were associated with primary lymphomas, and a +18 was predominantly found in secondary/simultaneous high-grade NHL. These results challenge earlier reports describing a high frequency of +3 in low-grade MALT-type NHL and indicate a possibly different genetic evolution pattern of primary and secondary/simultaneous high-grade lymphomas of primary mucosal origin.

Cell Nucleus↗
PubMed1998

A lymphohistiocytic variant of anaplastic large cell lymphoma with demonstration of the t(2;5)(p23;q35) chromosome translocation.

Cytogenetic investigations were performed in a case of a nodal malignant non-Hodgkin's lymphoma. Histopathological analysis from an involved lymph node as well as from a skin biopsy revealed a lymphohistiocytic variant of CD30-positive anaplastic large cell lymphoma (ALCL). A t(2;5)(p23;q35) chromosome translocation could be observed in all metaphases analysed. This finding was confirmed both by RT-PCR analysis of the NPM/ALK fusion protein and by positive staining with the p80(NPM/ALK) antibody. To the best of our knowledge, this is the first report of a t(2;5) documented by classic cytogenetics in the lymphohistiocytic variant of ALCL.

Adult↗