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Non-Hodgkin's lymphoma (NHL) occasionally involves the placenta, and information of such occurrence should be useful for management of the mother and fetus. We report the first case of anaplastic large cell lymphoma (ALCL) disseminated to the placenta. The diagnosis was made via excisional biopsy of cervical lymphadenopathy in a 20-year-old woman at 27 weeks' gestation. Involvement of the placenta was noted on gross examination after cesarean section delivery of a girl at 30 weeks' gestation. The ALCL was microscopically confined to intervillous spaces in a manner similar to previous reports of other NHLs. The immunophenotype was characteristic (CD30+, EMA+, BNH9+), and the now frequently associated t(2;5)(p23;q35) translocation with this lymphoma was detected by the recently produced monoclonal antibody ALK1 against the nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) chimeric protein. Complete remission was induced in the mother after delivery. Both mother and child are healthy at 10 years' follow-up. The case is reported in light of the sparse literature on lymphomatous involvement of the placenta.
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PMID:Anaplastic large cell lymphoma of maternal origin involving the placenta: case report and literature survey. 933 Dec 98

More than 60% of anaplastic large-cell lymphomas (Ki-1 lymphoma) are associated with a t(2;5)(p23;q35) translocation that produces an 80 kDa hyperphosphorylated chimeric protein (p80) derived from the fusion of the anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM). The NPM-ALK chimeric gene is an activated tyrosine kinase that has been shown to be a potent oncogene. We have developed a cellular model for the study of p80 action in rat 1a fibroblasts. Expression of cDNA's encoding NPM-ALK (p80) in rat 1a fibroblasts induces anchorage-independent growth in soft agar and promotes foci formation in culture. Cells expressing exogenous p80 showed significantly increased proliferation characterized by accelerated cell cycle entry into S-phase. Consistent with increased G0/G1 to S-phase transition, there is also marked up-regulation of cyclin A and cyclin D1 expression. In addition, p80 transformed cells showed elevated expression of several immediate early genes involved in cellular proliferation, including fos, jun, and c-myc. DNA binding analysis of nuclear extracts prepared from p80 transformed cells reveal marked up-regulation of AP-1 DNA binding activity. Functional AP-1-specific transfection assays also show up-regulation of AP-1-dependent transcriptional activation. These finding demonstrate that p80 transformed rat 1a fibroblast can be a highly useful model system for the molecular and biochemical characterization of the mechanisms of action of this interesting new oncogene.
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PMID:The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts. 933 49

Approximately 5% to 10% of all non-Hodgkin's lymphomas contain a t(2;5)(p23;q35) chromosomal rearrangement, which we have previously shown results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To assess the transforming potential of NPM-ALK in an animal model, we infected 5-fluorouracil-treated murine bone marrow using retroviral stocks and transplanted this infected marrow into lethally irradiated BALB/cByJ mice. Male mice were transplanted with bone marrow from female donors at 10 weeks of age, with 7 of the animals receiving marrow infected with a retroviral construct, pSR alphaMSVtkneo-NPM-ALK, that contains the human NPM-ALK cDNA, and 4 serving as a control group, receiving "empty" pSR alphaMSVtkneo-infected marrow. Whereas all mice in the control group were alive and well up to 11 months after transplantation, 4 of the 7 mice transplanted with marrow containing the NPM-ALK construct developed lymphoma within 4 to 6 months. Tumors arose in the mesenteric lymph nodes, with metastases to the lungs, kidneys, liver, spleen, and the paraspinal area. When cells from the tumors and bone marrow were transplanted into sublethally irradiated secondary recipients, 10 of these 13 mice developed tumors within 9 months. Immunoblot analysis of cell lysates using an ALK polyclonal antibody showed NPM-ALK expression in all tumors examined. Histologically, the tumors were composed of a uniform population of large immunoblastic cells with basophilic cytoplasm, centrally placed nuclei, and distinct nucleoli. Genotypic analysis showed that the tumors were B-lineage and clonal, with rearrangements of the Ig heavy- and kappa light-chain loci and no rearrangements of the T-cell receptor beta locus. Immunocytochemical studies confirmed the presence of IgM heavy chains and kappa light chains within the tumor cells. Thus, in this retroviral gene transfer model, NPM-ALK expression in mice causes B-lineage large-cell lymphoma, suggesting a direct causative role for this activated fusion tyrosine kinase in human lymphoma.
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PMID:Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. 937 69

The (2;5)(p23;q35) lymphoma-associated chromosomal translocation creates a novel fusion gene that incorporates parts of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and nucleophosmin genes. We report here that the product of this fusion gene accumulates within the nucleoli of neoplastic cells, and that previous reports of a predominantly cytoplasmic localization for the protein represent a tissue-processing artifact. However, nucleolar accumulation of nucleophosmin-ALK may not be necessary for its oncogenic action, because an ALK protein expressed in a lymphoma carrying a variant (1;2) chromosomal translocation did not accumulate in nucleoli. Furthermore, an engineered hybrid TPR-ALK protein can transform rodent fibroblasts and produce lymphomas in mice while remaining confined to the cytoplasm. We propose that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.
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PMID:Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation. 950 Apr 71

The expression of carbohydrate antigens, including sialyl Lewis X (SLEX) and BNH9 antigen, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion protein (p80NPM/ALK), cytotoxic cell-associated antigens, and Epstein-Barr virus (EBV) gene products in CD30+ anaplastic large cell lymphoma (ALCL) was investigated by immunohistochemistry and in situ hybridization (ISH) methods. The expression of SLEX and BNH9 antigen in ALCL was examined using CSLEX1 and BNH9, which specifically react with SLEX and oligosaccharides (H and Y haptens), respectively. SLEX was expressed in seven of 12 ALCL and BNH9 was positive for five of 12 ALCL. With respect to the relationship between SLEX and BNH9 expression in ALCL, some ALCL expressed both antigens, which suggests that they might have an increased or preserved activity of glycosyltransferase that is responsible for the synthesis of the type I or type II core sequences, although other ALCL expressed either SLEX or BNH9. To detect p80NPM/ALK in ALCL, the sections were immunostained with an anti-p80 antibody. Three of 12 ALCL expressed the NPM/ALK-encoded p80 protein. All three ALCL positive for p80NPM/ALK expressed SLEX and two of them were stained with BNH9, which raised the possibility that p80 overexpression may be involved in the aberrant expression of type I or type II chains with varying degrees of fucosylation or sialylation. While the expression of cytotoxic cell-associated antigens such as CD8, CD56 and T cell intercellular antigen 1 (TIA-1) in ALCL was immunohistochemically examined, none of the 12 ALCL expressed CD56 and only one case expressed CD8. TIA-1 was expressed in seven of 12 ALCL. Four of five BNH9-positive cases expressed TIA-1, suggesting that BNH9-positive cases tended to have TIA-1. In situ hybridization studies using an EBV-encoded RNA-1 (EBER-1) probe were performed on 12 ALCL to detect EBV in the lymphoma cells. EBER-1 signals were detected in the small lymphocytes but not in the lymphoma cells of two ALCL. However, latent membrane protein 1 immunoreactivity was found in one case. These results appear to indicate that there is no strong association between EBV and ALCL.
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PMID:Expression of carbohydrate antigens, p80NPM/ALK, cytotoxic cell-associated antigens, and Epstein-Barr virus gene products in anaplastic large cell lymphomas. 958 84

The t(2;5) (p23;q35) chromosomal translocation is found in about 40% of lymph node-based CD30+ anaplastic large cell lymphomas of T-cell or null-cell lineage. This translocation results in the expression of a fusion protein containing the catalytic domain of anaplastic lymphoma kinase (ALK) under the control of the promoter for nucleophosmin (NPM), a nucleolar phosphoprotein. Expression of ALK activity, normally absent in lymphocytes, is postulated to be involved in the pathogenesis of lymphomas bearing the t(2;5) translocation. Certain primary cutaneous lymphoproliferative disorders and Hodgkin's disease are also known to contain CD30+ large lymphoid cells. In order to determine the role of the t(2;5) translocation in these diseases, several investigators have employed a variety of techniques including cytogenetics, genomic Southern blot analysis, RNA- and DNA-based PCR assays, various forms of in-situ hybridization, and immunostaining for the p80 fusion protein encoded by the chimeric t(2;5) transcripts. These studies included approximately 415 cases of Hodgkin's disease, 65 cases of CD30+ primary cutaneous large cell lymphoma, and 38 cases of lymphomatoid papulosis. The aggregate results of these studies indicate that the t(2;5) translocation or other somatic mutations resulting in inappropriate expression of ALK are involved rarely if at all in the pathogenesis of Hodgkin's disease, but may be present in about 10% of cases of lymphomatoid papulosis and 20% of cases of CD30+ primary cutaneous large cell lymphoma. However, the t(2;5) has not been detected yet in any case involving multiple or secondary CD30+ lymphoproliferative disorders, thereby providing no evidence for a role in tumor clone progression. Additional studies will be needed to determine if t(2;5) status has any clinical significance for patients with CD30+ primary cutaneous lymphoproliferative disorders.
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PMID:Analysis of the t(2;5) (p23;q35) translocation in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease. 963 79

Anaplastic large cell lymphoma (ALCL) is an intermediate grade Non-Hodgkin's lymphoma (NHL) characterized by the frequent presence of the t(2;5)(p23;q35). This translocation fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a protein kinase gene (Anaplastic Lymphoma Kinase, ALK) on chromosome 2p23. In order to determine the frequency of t(2;5) we used a DNA polymerase chain reaction (PCR) amplification using genomic DNA, 5'-primers derived from the NPM gene, and 3'-primers derived from the ALK gene. The presence of amplifiable DNA in the samples was established with PCR and oligonucleotide primers designed to amplify a 3,016 bp fragment from the beta-globin locus. The t(2;5) PCR assay was established using DNA isolated from three t(2;5)-positive ALCL cell lines. Its ability to amplify genomic DNA prepared for routine molecular diagnostic use was validated using archival DNA from four ALCL tumors known to be t(2;5)-positive. Its sensitivity was established by serially diluting t(2;5)-positive DNA in normal DNA: amplicons were generated in 100% of reactions diluted 10(4)-fold (6-8 cells per tube) and in 30% of those diluted 10(5)-fold (0.6-0.8 cells per tube.) We subsequently analyzed archival genomic DNA extracted from 38 ALCL, 77 NHLs, 37 Hodgkin's lymphomas, and 9 lymphomatoid papuloses. The t(2;5) was detected in 6 ALCLs (16%, 95% confidence intervals 6%-31%), but not in any other lymphoma, or in lymphomatoid papulosis. By using the published sequence of the fourth NPM intron that is involved in t(2;5) and by sequencing the individual tumor amplicons and also the normal ALK intron that is involved in t(2;5), we established that all breakpoints involve the same introns in the ALK and NPM loci. Detailed analysis demonstrated that each translocation generates a unique breakpoint sequence, and suggested that sequence homology between the ALK and NPM intron sequences may be involved in the translocation. We conclude that genomic DNA-PCR is useful for the detection of t(2;5) that in our patient population is restricted to ALCL and is not detectable in other NHL, Hodgkin's disease, or lymphomatoid papulosis. More work is needed to determine the prognostic significance of t(2;5), and to establish the utility of the genomic DNA PCR in monitoring minimal residual disease.
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PMID:Genomic DNA amplification and the detection of t(2;5)(p23;q35) in lymphoid neoplasms. 964 64

Large-cell anaplastic lymphoma is a subtype of non-Hodgkin's lymphoma characterized by the expression of CD30. More than half of these lymphomas have a chromosomal translocation, t(2;5), that leads to the expression of a hybrid protein comprised of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK). Here we show that transfection of the constitutively active tyrosine kinase NPM-ALK into Ba/F3 and Rat-1 cells leads to a transformed phenotype. Oncogenic tyrosine kinases transform cells by activating the mitogenic signal transduction pathways, e.g., by binding and activating SH2-containing signaling molecules. We found that NPM-ALK binds most specifically to the SH2 domains of phospholipase C-gamma (PLC-gamma) in vitro. Furthermore, we showed complex formation of NPM-ALK and PLC-gamma in vivo by coimmunoprecipitation experiments in large-cell anaplastic lymphoma cells. This complex formation leads to the tyrosine phosphorylation and activation of PLC-gamma, which can be corroborated by enhanced production of inositol phosphates (IPs) in NPM-ALK-expressing cells. By phosphopeptide competition experiments, we were able to identify the tyrosine residue on NPM-ALK responsible for interaction with PLC-gamma as Y664. Using site-directed mutagenesis, we constructed a comprehensive panel of tyrosine-to-phenylalanine NPM-ALK mutants, including NPM-ALK(Y664F). NPM-ALK(Y664F), when transfected into Ba/F3 cells, no longer forms complexes with PLC-gamma or leads to PLC-gamma phosphorylation and activation, as confirmed by low IP levels in these cells. Most interestingly, Ba/F3 and Rat-1 cells expressing NPM-ALK(Y664F) also show a biological phenotype in that they are not stably transformed. Overexpression of PLC-gamma can partially rescue the proliferative response of Ba/F3 cells to the NPM-ALK(Y664F) mutant. Thus, PLC-gamma is an important downstream target of NPM-ALK that contributes to its mitogenic activity and is likely to be important in the molecular pathogenesis of large-cell anaplastic lymphomas.
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PMID:Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. 981 83

The t(2;5) (p23;q35) that is frequently detected in anaplastic large cell lymphoma (ALCL) fuses the nucleophosmin (NPM) gene on chromosome 5 to a novel tyrosine kinase gene designated anaplastic lymphoma kinase (ALK) on chromosome 2. The fusion of NPM and ALK genes results in the production of chimeric transcripts containing NPM amino-terminal sequences fused to the ALK carboxy-terminal catalytic domain. Because fusion transcripts and proteins in almost all t(2;5)-positive cell lines and tumors are identical, it is likely that the chromosomal breaks involve the same introns of NPM and ALK genes. We have previously developed a long-range genomic DNA-PCR assay to amplify the genomic NPM-ALK break points. Using high-molecular-weight DNA extracted from 2 ALCL cell lines and from 9 primary ALCLs known to be t(2;5)-positive, we have demonstrated that all 11 amplicons were of different sizes, suggesting that the t(2;5) break points were unique and involved the same introns on both chromosomes. We decided to confirm this and map the t(2;5) break points by genomic DNA sequencing. Using the same long-range DNA-PCR technique, primers from the ALK locus, and normal genomic DNA, we sequenced the ALK intron involved in t(2;5). We subsequently sequenced all 11 amplicons from t(2;5)-positive ALCL cell lines and tumors. Comparison of the sequences derived from ALCL amplicons with the published sequences of intron 4 from the NPM locus (910 bp) and with the newly sequenced intron from the ALK locus (1935 bp) accurately mapped all break points and demonstrated that their nucleotide sequences were unique. We conclude that the genomic t(2;5) break points can be easily mapped by sequencing the amplicons generated from genomic DNA with long-range PCR and that they are unique for each patient. The sequences of the break points and of the newly identified ALK intron may be useful in the construction of patient-specific primers for monitoring and determination of the clinical relevance of minimal residual disease.
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PMID:Mapping of genomic t(2;5)(p23;q35) break points in patients with anaplastic large cell lymphoma by sequencing long-range PCR products. 984 24

The translocation t(2;5), which leads to the fusion of the nucleophosmin gene (NPM) on chromosome 5q35 to the receptor kinase ALK on chromosome 2p23, is found in CD30+ anaplastic large cell lymphomas and some cases of B-cell lymphoma. Hodgkin's disease (HD) is a malignant lymphoma characterized by large multinucleated tumour cells, Hodgkin and Reed-Sternberg (H&RS) cells, surrounded by a dense lymphohistiocytic infiltrate. Our group recently demonstrated NPM/ALK fusion cDNAs by single-cell RT-PCR in < 3% of CD30+ tumour cells in 2/9 cases of HD. To further delineate the relevance of this finding for HD, we studied the occurrence of NPM/ALK fusion genes in peripheral blood cells of healthy donors by RT-PCR. NPM/ALK fusion cDNAs were found by RT-PCR in 14/29 healthy individuals and confirmed by hybridization with a breakpoint-specific oligonucleotide. Due to the low rate of NPM/ALK-positive cells in the peripheral blood of positive individuals, an assignment to a defined cellular subpopulation was not possible. We conclude that NPM/ALK fusion genes are present in peripheral blood cells of healthy donors. After t(14;18) and t(9;22), t(2;5) represents the third example of tumour-associated translocation products in blood cells of apparently healthy donors. The implications of this finding are discussed.
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PMID:Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. 988 32


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