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Therapy for the inflammatory bowel diseases increasingly includes the use of immune-modifying and biologic therapies. Recently, in young patients with IBD, an association has been noted between the use of infliximab along with concomitant purine analogues and the development of hepatosplenic T-cell lymphoma (HSTCL)-a rare and all but incurable form of non-Hodgkin's lymphoma. This report briefly reviews the issue of lymphoma and IBD therapy. Additionally, a description of HSTCL and a summary of the known cases of this apparent therapeutic complication are presented. Clinical options in light of this new information are explored.

Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.

TEL2/ETV7 is highly homologous to the ETS transcription factor TEL/ETV6, a frequent target of chromosome translocation in human leukemia. Although both proteins are transcriptional inhibitors binding similar DNA recognition sequences, they have opposite biologic effects: TEL inhibits proliferation while TEL2 promotes it. In addition, forced expression of TEL2 but not TEL blocks vitamin D3-induced differentiation of U937 and HL60 myeloid cells. TEL2 is expressed in the hematopoietic system, and its expression is up-regulated in bone marrow samples of some patients with leukemia, suggesting a role in oncogenesis. Recently we also showed that TEL2 cooperates with Myc in B lymphomagenesis in mice. Here we show that forced expression of TEL2 alone in mouse bone marrow causes a myeloproliferative disease with a long latency period but with high penetrance. This suggested that secondary mutations are necessary for disease development. Treating mice receiving transplants with TEL2-expressing bone marrow with the chemical carcinogen N-ethyl-N-nitrosourea (ENU) resulted in significantly accelerated disease onset. Although the mice developed a GFP-positive myeloid disease with 30% of the mice showing elevated white blood counts, they all died of T-cell lymphoma, which was GFP negative. Together our data identify TEL2 as a bona fide oncogene, but leukemic transformation is dependent on secondary mutations.

Bexarotene is a retinoid drug that is approved for the treatment of cutaneous T-cell lymphoma. We report 6 cases in which the initiation of bexarotene therapy for cutaneous T-cell lymphoma was temporally associated with the progression of internal disease despite improvement in cutaneous signs and symptoms. It is possible that bexarotene contributed to this progression. Although bexarotene therapy may alleviate symptoms and signs of cutaneous T-cell lymphoma, careful surveillance of lymph nodes and solid organs during treatment is advised.

BCL6, a gene on chromosome 3, band q27, encodes a zinc finger transcriptional repressor that is needed for germinal center formation and has been implicated in the pathogenesis of some human lymphomas when it is mutated or involved in chromosomal rearrangements. To explore further the mechanisms of action of BCL6 in lymphomagenesis, we developed a transgenic mouse model mimicking a common translocation, the t(3, 14)(q27;q32), in human lymphomas. The transgenic mice develop normally and express the transgenic BCL6 protein constitutively in lymphocytes. A small fraction of the animals develop B and T cell lymphomas after a long latency period, but the incidence is dramatically enhanced following administration of N-ethyl-N-nitrosourea, a carcinogen that induces DNA mutations. The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice. Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.

There have been only five reported cases of primary posttransplant T-cell lymphoma. We report the first case associated with the use of sirolimus (Rapamycin, Wyeth-Ayerst, Philadelphia, PA). The patient, receiving prednisone, cyclosporine, and sirolimus treatment, developed ascites, diarrhea, and weight loss 7 months after his second renal transplant. Tissue obtained at laparotomy established the diagnosis of primary T-cell lymphoma. Latent membrane protein-1 for Epstein-Barr virus was negative, but in-site hybridization test for Epstein-Barr-encoded RNA was positive. Despite aggressive chemotherapy, the patient died 8 months posttransplant. This is the sixth reported case of primary intestinal posttransplant T-cell lymphoma, but it is the first case associated with the use of sirolimus. The incidence of posttransplant lymphoproliferative disease in patients receiving sirolimus should be studied.

The transduction of exogenous hepatocyte growth factor (HGF) genes to spleen T lymphocytes and the immune effects of syngeneic spleen graft on spleen lymphoma cells were studied in LEW/Sea rats. Three different systems were designed. (1) Six female rats and six male rats received irradiated spleen graft and were followed for 7 months. (2) Five female rats and six male rats received intra-peritoneal (i.p.) injections of the Lewis red cells incorporated 20-bp HGF genes and anti-interleukin-6 (IL-6) antibody (Ab) with spleen graft and were followed for 5.5 months. (3) Four females and five males received i.p. injections of the Lewis red cells incorporated 20-bp HGF genes and anti-IL-6 Ab without spleen graft and were followed for 5.5 months. Hemato-pathological analyses, flow cytometer analyses of gamma-delta (gammadelta) T-cell receptor (TCR)-positive lymphocytes and reverse-transcription-polymerase chain reaction (RT-PCR) of TCRgamma gene, TCRValpha3 gene and apoptotic genes were performed. Results showed that one of the six females received irradiated spleen graft developed nodal gamma-delta (gammadelta) T-cell pre-lymphoma with 100% of gammadelta TCR+ lymphocytes in the mesenteric lymph nodes. One female injected with the HGF genes and anti-IL-6 Ab and grafted spleen died of advanced hepatosplenic gammadelta T-cell lymphoma at 3.5 month observation. All the five males injected with the HGF genes and anti-IL-6 Ab without spleen graft developed early hepatosplenic gammadelta T-cell lymphoma at 5.5 month observation. In two rats with spleen graft and the two rats without spleen graft, which were injected with the HGF genes and anti-IL-6 Ab, the lymphoma was suspected uncertainly with activated TCRValpha3 mRNA. The i.p. injections of HGF genes, which were incorporated in the red blood cells, triggered hapatosplenic gammadelta T-cell lymphoma. Surviving spleen graft rejected the lymphoma cells, but not in rats rejected the graft. Spleen graft was a good organ transplantation to expect graft versus lymphoma effects.

The mouse Polycomb-group gene, embryonic ectoderm development (eed), appears to regulate cellular growth and differentiation in a developmental and tissue specific manner. During embryogenesis, eed regulates axial patterning, whereas in the adult eed represses proliferation of myeloid and B cell precursors. The present report demonstrates two novel functional activities of eed: alteration of thymocyte maturation and suppression of thymic lymphoma development. Mice that inherit the viable hypomorphic 17Rn5(1989SB) eed allele sustain a partial developmental block at or before the CD4(-)CD8(-)CD44(-)CD25(+) stage of thymocyte differentiation. Furthermore, mice that are homozygous or heterozygous for the hypomorphic eed allele have an increased incidence and decreased latency of N-methyl-N-nitrosourea-induced thymic lymphoma compared to wild-type littermates. These findings support the notion that Polycomb-group genes exert pleiotropic effects dictated by developmental stage and cellular context.

Breast lymphoma is a rare entity consisting mostly of B-cell lymphomas that affects older women. Very few cases of breast lymphomas of T-cell origin have been reported. Even fewer cases of breast lymphomas have been reported in women who have received breast implants. Silicone, a frequent component of breast implants, has been extensively investigated as a possible etiologic agent for some neoplasias and autoimmune disorders, including non-Hodgkin's lymphoma. We herein report two unusual cases of anaplastic large cell lymphoma of T-cell phenotype developing in the breasts of women who had received breast implants.

Familial occurrence of nasal NK/T-cell lymphoma (NNKTCL) in pesticide users is presented. The proband (71 years old, male) and son (39 years old) were both diagnosed with NNKTCL within interval of 26 months. Laboratory data showed slight anemia, with no abnormal cells in peripheral blood. They and their wives were farmers and used large amounts of pesticides (fungicides and insecticides) in the hothouse. NNKTCL did not develop in the wives. Proband's father was diagnosed with malignant lymphoma of the neck and died of the disease. Genetic analyses of the peripheral blood leukocytes and tumor tissues did not show p53 and k-ras gene mutations and microsatellite instability. Metaphase cells from peripheral blood leukocytes bore specific marker chromosomes (father, 44XY,-14,-17,-18,-22,+2mar; son, 46XY,-17,+1mar). Environmental exposures to pesticides in conjunction with familial or genetic factors might increase the risk for NNKTCL.

To study the oncogenic activity of cyclin E in an in vivo system we generated transgenic mice expressing high levels of cyclin E in T-lymphocytes by using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with Emu L-myc transgenic mice but developed hyperplasia in peripheral lymphoid organs at later age with an incidence of 27%. When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice we could find an expected activating point mutation in the Ki-ras gene (12.5%). In contrast, the same mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular ras genes are present and activated. This would be consistent with our previous finding that cyclin E and Ha-Ras cooperate in focus formation assays in rat embryo fibroblasts.

Posttransplant lymphoproliferative disorders are typically of B cell origin, whereas T cell lymphomas have been rarely documented. We present a case of a non-Hodgkin's T cell lymphoma involving the intestinal graft of a multivisceral transplant patient. The patient was a 7-year-old girl who underwent at age 5 a multivisceral transplant secondary to short gut syndrome. Baseline immunosuppressive therapy consisted of FK506, methylprednisone, and mycophenolate mofetil. At 2 years posttransplant she presented with fever, diarrhea, nausea, and vomiting. Multiple endoscopic biopsies revealed a severe intensity, diffuse and focally nodular lymphocytic infiltrate composed predominantly of small, monomorphic lymphoid cells with scattered plasma cells and abundant eosinophils. Immunohistochemically, the majority of the lymphoid cells expressed the pan T cell marker CD3. Southern blot analysis revealed rearrangement of the T cell receptor beta chain gene, with germline configuration of the heavy immunoglobulin chain gene, confirming a clonal T cell genotype. In situ hybridization for Epstein Barr virus revealed rare positive lymphoid cells, that were negative with CD3 by immunohistochemical staining. A detailed clinico-radiological work-up revealed no other sites of involvement by the lymphomatous process. After the diagnosis of posttransplant lymphoproliferative disorder, immunosuppression was reduced with a subsequent partial improvement in the endoscopic appearance of the graft and a focal decrease in the lymphocytic infiltrate seen in the follow-up biopsies. Repeat gene rearrangement studies demonstrated germline configuration of both the T cell receptor beta chain gene and the heavy chain immunoglobulin. gene. To our knowledge, this represents the first description of a T cell lymphoma affecting the intestinal allograft of a multivisceral transplant patient.

Within 180 days after injection with N-methyl-N-nitrosourea (MNU), 83.5% of AKR/J mice and 37.5% of BALB/cJ mice developed T-lymphoma. The high tumor incidence was a dominant trait, as 93% of MNU-injected F1 mice developed T-lymphoma. A genome screen of 285 MNU-injected F2 mice identified a locus, designated T-lymphoma Induced 1 or Tli1, in a approximately 10-cM interval on central Chr 1 between D1Mit87 and D1Mit423 with significant linkage to the incidence of MNU-induced T-lymphoma (P = 0.0004). Injection of BALB/cJ.AKR/J-Tli1 congenic mice with MNU confirmed the presence of Tli1 on central Chr 1. Mice homozygous for the BALB/cJ allele (Tli1bb) were over-represented in the tumor-free F2 mice, while the inheritance of parental alleles of Tli1 in tumor-bearing mice was close to expected. This suggests that the Tli1b allele is recessive and suppresses MNU-induced T-lymphoma development in BALB/cJ mice and in Tli1bb F2 mice. Furthermore, the kinetics of lymphoma development in BALB/cJ and the Tli1 congenic mice suggests that Tli1b acts to suppress lymphomas developing late after injection with MNU. Two known genes that map in the identified genomic interval on central Chr 1 are candidates for Tli1:IL10, encoding the lymphokine IL10, and Cmkar4, encoding the chemokine receptor CXCR4.

Oral administration of propylnitrosourea (PNU) in drinking water induces high incidence of lympho-haemopoietic malignancies in rats. Previously we reported that F344 strain rats were highly susceptible to T-lymphomas, and LE/Stm rats, to erythro- or myeloid leukaemias. For analysis of the genetic factors determining types of diseases, we have established LEXF recombinant inbred strains of rats comprising 23 substrains, each derived from intercross between F344 and LE/Stm rats. Rats of 23 LEXF substrains were given PNU, and the development of tumours was observed. The overall incidence of haemopoietic tumours ranged from 100% to 66.7%, and the fractions of T-lymphomas, from 100% to 4%, showing a continuous spectrum. Based on the genetic profile published as a strain distribution pattern table for the LEXF, we screened the potential quantitative trait loci involved in determination of the types of disease and length of the latency period. Statistical calculation was performed using the Map Manager QT software developed by Manly. Four loci, on chromosome 4, 7, 10 and 18, were suggested to associate with the T-lymphoma susceptibility and three loci, on chromosome 1, 5 and 16, with the length of the latency period. These putative loci were further examined in backcross (F344 x LE)F1 x LE. Among seven loci suggested by the recombinant inbred study, three loci, on chromosome 5, 7 and 10, were significantly associated with T-lymphomas and another locus on chromosome 1, just weakly. These observations indicate that PNU-induced lymphomagenesis is a multifactorial genetic process involving a number of loci linked with susceptibility and resistance.

The tumor-suppressing phenotype of p53 is thought to be due to its accumulation in response to DNA damage and resultant cell cycle arrest or apoptosis. scid/scid mice are defective in DNA double-strand break repair due to a mutation in DNA-dependent protein kinase (DNAPK). Treatment of scid/scid mice with gamma radiation or N-ethyl-N-nitrosourea resulted in approximately 86% incidence of T-cell lymphomas, compared with <6% in wild-type mice. The incidence of other tumor types was not increased in scid/scid mice, suggesting that the types of DNA double-strand break that are unrepaired in these mice are not strongly carcinogenic. To determine whether mutations in DNAPK and p53 interact, we examined mice deficient in both genes. Both scid/scid p53-/- and scid/scid p53+/- mice spontaneously developed lymphomas at shorter latency than did mice with either defect alone. Loss of the wild-type p53 allele was observed in 100% of tumors from scid/scid p53 +/- mice, indicating strong selection against p53. In contrast, p53 was not inactivated in lymphomas from scid/scid p53+/+ mice. Exposure of these tumor-bearing mice to gamma radiation resulted in p53 protein accumulation and high levels of apoptosis in all tumors that were not observed in tumors from scid/scid p53+/- mice. Thus, there was a bifurcation of molecular pathways to tumorigenesis. When p53 was heterozygous in the germ line, loss of the wild-type allele occurred, and the tumors became apoptosis resistant. When p53 was wild type in the germ line, p53 was not inactivated, and the tumors remained highly apoptosis sensitive.

A patient with idiopathic thrombocytopenic purpura (ITP) developed T-cell lymphoma while undergoing steroid therapy. We examined the relationship between the patient's serum thrombopoietin (Tpo) level, platelet count, megakaryocyte number and CFU-Meg number during the second 5 d course of chemotherapy for lymphoma in which megakaryopoiesis switched from ITP phase to amegakaryocytic phase. The patient's platelet count was temporarily elevated but CFU-Meg numbers were markedly suppressed, and megakaryocyte numbers were decreased in this period, whereas serum Tpo level was not suppressed despite an increased platelet count, indicating that serum Tpo level is mainly regulated by megakaryocyte mass.

Mutations of p53 and ras genes were analyzed in 40 and 31 1,3-butadiene (BD)-induced lymphomas of B6C3F1 mice (BLFs), respectively, and in 63 2',3'-dideoxycytidine-induced lymphomas, which were collected from B6C3F1 (n = 16) or NIH Swiss mice (DLSs; n = 47). The frequencies of K- and N-ras mutations in BLFs (32 and 13%, respectively) were higher than those in DLSs (13 and 2%, respectively). Seven of 10 K-ras-mutated BLFs contained codon 13 CGC mutations, whereas no mutation in K-ras codon 13 was detected in DLSs, suggesting that the codon 13 CGC mutation is specific for BD exposure. Interestingly, 8 of 13 BLFs with ras mutations were from low-dose (< or = 200 ppm) or stop-exposure (26 weeks) groups. These results suggest that ras mutations play an important role in the development of BD-induced lymphoma and may represent an early event. Analysis of genetic alterations in exons 5-8 of the p53 gene revealed mutations in seven of the BLFs and three of the DLSs. All seven BLFs carrying p53 mutations were collected from the high-dose (625 ppm) continuous exposure group, which might indicate that p53 is involved in the progression of BD-induced lymphoma and in late stage of lymphomagenesis. Mutations in ras and p53 genes are relatively infrequent in 2',3'-dideoxycytidine-induced lymphomas, suggesting that other genes must be involved.

Since nonrandum chromosome changes in neoplastic cells have proven to be good indicators of gene alteration site related to transformation, the authors examined the chromosomes of T-cell lymphomas induced in mice strain RF/J with methylnitrosourea (MNU). All treated mice developed thymic lymphomas within 10 weeks after injection. Chromosomes of the thymus cells were examined at intervals before and during lymphoma development, as well as after the lymphomes were transmitted in syngeneic and nude mice for a period up to 424 days. In preparations made from the thymus and transmitted cells in both syngeneic and nude mice nonrandom quantitative and structural alterations were found involving X, 15, 14, 3, 12 chromosomes (showing in decreasing order of the frequency of alterations), suggesting that these chromosomes carry genes (oncogenes or tumor suppressor genes). MNU thus appears not only to be tissue specific but also chromosome specific in its effects. The neoplastic growth is resulted from a large number of sets of altered genes. Thus, if MNU preferentially target some of these sites, the probability of its induced transformation would be high. This may be the reason to explain its high clastogenicity.

We report here an unusual post-thymic T-cell neoplasia of the spleen associated with a rapidly progressive haemophagocytic syndrome. The lymphoma was classified as a medium- to large sized pleomorphic T-cell lymphoma with angiocentric tendency (CD3+, CD43+, CD45RO+ CD45+). Clonality was confirmed by PCR and revealed rearrangement of the T-cell receptor gamma chain. Serological tests excluded a recent EBV infection and in situ hybridization with the EBER probe was negative. Haemophagocytic syndrome was the initial finding in an otherwise symptomless patient and this deteriorated with progression of the T-cell malignancy. Both, the T-cell lymphoma and the haemophagocytic syndrome remained unaffected by chemotherapy. Splenic gamma/delta T-cell lymphoma associated with haemophagocytosis is an uncommon entity which has until now not been widely recognized.

2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.

The mouse Lsp1 gene encodes a 330 amino acid intracellular F-actin binding protein. Previously we showed that the mouse and human Lsp1 genes are expressed in normal B-cells and T-cells, including Thy1+ thymocytes and in normal macrophages and neutrophils. No or little LSP1 RNA and protein was found in a series of transformed mouse and human T-lymphoma cell lines, although normal antigen and lymphokine dependent T-cell lines expressed the Lsp1 gene. Here we show by Northern analysis that three mature antigen independent T-cell lines (CTLL-2, HT-2 and 532.10) which grow in the presence of lymphokine only, do not express LSP1 RNA, while mature resting and activated lymph node T-cells express high levels of LSP1 RNA. To determine whether the down-regulation of LSP1 expression is an early event which occurs in vivo in the tumor, rather than as a consequence of in vitro propagation of T-lymphoma cells, we analyzed LSP1 expression in primary T-lymphomas induced in AKR/J or AKR/J x BALB/cJ mice by a single intraperitoneal (i.p.) injection with 75 mg N-methyl-N-nitrosourea (MNU) per kg body-weight. Two- color Fluorescence Activated Cell Sorter (FACS) analysis showed that all tumors had an immature CD4+/CD8+ double positive (DP) phenotype. Many tumors contained a substantial population of CD4+ single positive (SP) cells. Since these cells may be infiltrating lymphocytes which can be expected to express the Lsp1 gene at a high level these tumors were not included in our analysis. Nineteen tumors were analyzed for Lsp1 gene expression and 13 contained reduced levels of LSP1 RNA, ranging from 4% to 44% of those found in age-matched normal thymus. Six tumors showed either no or only a small reduction in LSP1 RNA. These tumors had developed later than those expressing low levels of LSP1. The level of LSP1 RNA in tumors developing <110 days after injection of MNU was 19.1% +/- 5.2 (mean +/- SEM), while the level of LSP1 in later tumors was 78.4% +/- 13.0 (P = 0.004). Similar data were obtained when the expression of LSP1 protein was analyzed. These findings extend our previous data in several ways. First, they suggest a correlation between the down-regulation of LSP1 expression and abnormal regulation of growth or survival of immature and mature T-lymphocytes. Second, they show that down-regulation of the Lsp1 gene in transformed T-cells is not the result of prolonged in vitro culture, but occurs in the majority of primary tumors. Third, they show that there are two classes of T-lymphoma, which differ in their expression of LSP1 RNA and that the down-regulation of LSP1 is specifically associated with the early appearance of T-lymphoma after injection with MNU. This strongly suggests that the absence or reduced expression of LSP1 contributed to the transformation process and argues against the possibility that loss of LSP1 expression is a mere inconsequential epigenetic event.

The AKR inbred mouse strain displays a high incidence of spontaneous T cell lymphomas that arise predominantly in the thymus of 6 to 12-month-old mice. Heterogenous nonacute transforming retroviruses are associated with the etiology of the disease: the endogenous ecotropic viruses (inherited in AKR mice at two non-linked chromosomal loci, Akv-1 and Akv-2), the xenotropic virus and recombinant viruses. Prevention of spontaneous T cell lymphomagenesis in AKR mice by passive anti-viral immunotherapy was accomplished by suppressing endogenous ecotropic virus release. Treatment with monoclonal antibody Hy-72 reacting only with Akv1 type ecotropic viruses, or with mAb 18-5 with specificity for both ecotropic and MCF recombinant virus envelope glycoprotein (administered from birth for 10 days) inhibited similarly T cell lymphoma development. A reduced thymus cellularity observed in these mAb treated mice coincided with reduced level of earliest intrathymic low CD4 precursor population in their thymus. The role of endogenous viruses (MuLV) and presence of potential lymphoma cells (PLCs) (identified among bone marrow cells of untreated AKR mice) in enhanced T cell lymphomagenesis in AKR mice, triggered by different leukemogenic agents, was evaluated. Intrathymic injection of the radiation leukemia virus variant A-RadLV or administration of methylnitrosourea resulted in a high lymphoma incidence within a short latent period of 80-100 days irrespective of the presence or absence of MuLV or PLCs in these treated mice. Thus, a direct action of these agents on thymocytes seems to occur. The high susceptibility of untreated AKR mice to radiation induced T cell lymphomagenesis was not affected by pretreatment with mAb Hy-72; in contrast to markedly reduced sensitivity following pretreatment with mAb 18-5 (15 vs 100%). The mAb 18-5 induced resistance to radiation lymphomagenesis seems to be related to defects in the bone marrow stem cell pool as well as in the thymus microenvironment of mAb 18-5 treated mice. Thus, different developmental pathways are involved in enhanced T cell lymphomagenesis in AKR mice.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), is a potent inhibitor of HIV replication, and AIDS patients receiving ddC experience clinical improvement without significant hematologic toxicity. Repeated ddC administration (1,000 mg/kg per day) for 13 wk produces an increased incidence of thymic lymphoma in B6C3F1 mice. Previous studies reveal a common link between chemically induced and genetically associated models of mouse thymic lymphoma that involves a defect in a subpopulation of primitive hematopoietic progenitor cells. This defect is characterized by suppression of a subpopulation of IL-3-responsive cells and ablation of stem cell factor synergy with GM-CSF. The present study was undertaken to ascertain whether ddC produces the same pattern of bone marrow toxicity in mice, and whether this effect is observed in rat and human bone marrow. ddC exposure in vivo and in vitro produced a select suppression of murine CFU identical to that previously described for other models of mouse thymic lymphoma. In contrast, this selective CFU suppression was not observed in rat and human bone marrow or in CD34+ cells. These studies suggest that the mouse may not be a good predictive model for ddC hematotoxicity in humans and that susceptibility to the development of thymic lymphoma may be unique to the mouse.

Effects of barbital (BB) on neuro-oncogenesis were examined in a rat transplacental carcinogenesis model. Pregnant F344 rats were divided into 7 groups. Dams in group I received subcutaneous injections of 10 mg/rat 1-butyl-1-nitrosourea (BNU) on the days 15, 18 and 21 of pregnancy and dams in groups II-IV, 1mg/rat BNU on the same time schedule. In addition to the treatment with BNU, dams in group IV were given 0.125% BB solution as their drinking water from the day 12 of pregnancy to parturition. Offspring in groups III and IV received 0.125% BB solution as drinking water from 4 weeks of age until the termination of the study. Animals in groups V and VI were given 0.25% and 0.125% BB solutions, respectively, in the peri- and postnatal period without BNU treatment. Dams in group VII received 250 mg/kg BB subcutaneously on the days 15, 18 and 21 of pregnancy. Offspring in all groups were observed until 105-116 weeks of age. High yields of neurogenic tumors, such as gliomas and neurinomas, were observed in group I. In groups II, III and IV, single cases of a chordoma, a granular cell tumor, and a neurinoma and a malignant reticulosis, which are known to occur spontaneously, were noted, although no gliomas were found. No neurogenic tumors were observed in groups V-VII. With regard to lesions other than those in neurogenic organs, a significant increase in liver tumors was observed in group III compared to group II. In contrast, lung tumors were not found in group III, while they were observed in groups II and IV. These results suggest that BB has no neuro-carcinogenic activity in the rat transplacental carcinogenesis model.

Previous reports have suggested that nodular lymphocyte predominance Hodgkin's disease (NLPHD) is a germinal center-derived B-cell lymphoma that is distinct from other types of Hodgkin's Disease. A relationship between NLPHD and simultaneous or subsequent development of large-cell (LC) non-Hodgkin's lymphoma (NHL) has been established. Both Reed-Sternberg cell variants in NLPHD and NHL cells in these cases express B-cell-associated antigens, and in some cases the B-cell lineage of the NHL has been confirmed by immunoglobulin gene rearrangement studies. The B-cell phenotype and the indolent course of both lymphomas suggest histologic progression of NLPHD to B-cell NHL, rather than a de novo LCNHL unrelated to Hodgkin's Disease. We report a unique case of T-large-cell lymphoma (TLCL) following successful chemotherapy of NLPHD. A 54-year-old male was treated with seven cycles of mechlorethamine, vincristine, procarbazine, prednisone chemotherapy for NLPHD and 4 years later developed recurrent adenopathy. Lymph node biopsy showed a diffuse LCNHL. Frozen section immunotyping and gene rearrangement studies confirmed the diagnosis of TLCL. To our knowledge, this case represents only the second report of TLCL associated with NLPHD and is of significance in that: (1) it demonstrates that T-cell neoplasia can occur in the setting of NLPHD; (2) this case does not appear to represent histologic progression of NLPHD and most likely represents de novo disease that may be secondary to chemotherapy; and (3) the clinical course may differ from the favorable prognosis seen in NLPHD associated with B-cell NHL.

Transgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo. Although no major histological or morphological modifications of the lymphoid system were observed in most animals, approximately 7% of transgenic mice developed thymic lymphomas at the age of 3-9 months. The tumor cells, which were clonal, with unique T cell rearrangements, were double positive for the expression of CD4 and CD8. The need for additional transforming events, suggested by the low incidence of spontaneous tumors, was further indicated by the high susceptibility of the transgenic animals to injections of low doses of N-methyl-N-nitrosourea, a chemical carcinogen with a thymic tropism. Expression of interleukin 9 was required for optimal tumor growth in vivo, as one of the tumors studied, which had lost the transgene, was much more efficiently transplanted into transgenic than in normal mice. Moreover, the in vitro proliferative activity of interleukin 9 on cell lines derived from such transgene-negative tumors suggests that an autocrine loop mediates the proliferation of these cells in vivo. Taken together, these results indicate that dysregulated IL-9 expression could be involved in the development of some T cell malignancies.

From a lymphoid tumour induced by 7,12-dimethylbenz-[a]-anthracene (DMBA) + methyl-N-nitrose-N-urea (MNU) in an [AKR Rb(6.15) x CBAT6T6]F1 mouse, a macrophage- monocyte line (KT-10) was isolated. Following ethyl methanesulfonate (EMS) treatment, a bromodeoxyuridine (BUdR) resistant subline was selected. Serial propagation of this line in vitro in the presence of BUdR (28 months) with periodic cytogenetic and molecular examinations, has led to the definition of four successive stages. During stage I, the cells were trisomic for chromosome 15. They contained Rb(6.15) and Rb(del6.15) of AKR and T(14;15) of CBA origin. Southern blotting showed the presence of both germline (G) and rearranged (R) c-myc. At stage II, Rb(del6.15) has duplicated. Both Rb(6.15) and T(14;15) persisted together with G-myc and R-myc. In stage III, the CBA-derived T(14;15) was lost, in parallel with G-myc. At this stage, a Dic.In(6.15) was detected. One of its arms was cytogenetically identical with the long arm of In(6.15) in the variant IgK/myc translocations. This chromosome carried R-myc and IgK in juxtaposition, as indicated by comigration on pulsed field electrophoresis (PFGE). At stage IV, the R-myc carrying AKR-derived chromosome 15s were present in six copies. Possible relationships between the increasing R/G myc ratio and changed growth characteristics in vivo and in vitro are discussed.

Nitrosoureas form O6-alkylguanine-DNA adducts that are converted to G to A transitions, the mutation found in the activated ras oncogenes of nitrosourea-induced mouse lymphomas and rat mammary tumors. These adducts are removed by the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Transgenic mice that express the human homolog of this protein in the thymus were found to be protected from developing thymic lymphomas after exposure to N-methyl-N-nitrosourea. Thus, transgenic expression of a single human DNA repair gene is sufficient to block chemical carcinogenesis. The transduction of DNA repair genes in vivo may unravel mechanisms of carcinogenesis and provide therapeutic protection from known carcinogens.

We report a case of phenytoin induced lymph node enlargement with changes in both the lymph nodes and bone marrow suggestive of T-cell non-Hodgkin's lymphoma. The condition resolved after phenytoin withdrawal and the patient has no evidence of disease on bone marrow biopsy 15 months later.

Patients receiving immunosuppressive treatment show an increased incidence of malignant lymphoproliferative disease, mainly in the form of B-lymphomata, on account of constant antigen stimulation from an implanted organ and/or impaired immunological defense which permit cells which have undergone mutation or have been transformed by viruses to proliferate. Malignant T-proliferative disease is rare in this patient category. The authors present a case in which a man treated with azathioprin and prednisone who had been well and without symptoms of rejection during a total of seven years after renal transplantation, which suggests that the T-cell neoplasia was due to the immunosuppressive treatment.

Transgenic mice overexpressing the pim-1 oncogene in their lymphoid compartments are predisposed to T-cell lymphomagenesis but only to the extent that approximately 10% of the transgenic mice develop lymphomas within 34 weeks after birth. Recently, we have shown that lymphomagenesis in pim-1 transgenic mice can be accelerated by infecting pim-1 transgenic mice with murine leukemia viruses or by treating the mice with a relatively low dose of 60 mg of the carcinogen N-ethyl-N-nitrosourea (ENU) per kg of body weight. Here we describe the incidence of tumors as a function of the dose of ENU. Either 200, 15, 4, 1, or 0.1 mg/kg ENU was injected into transgenic and control mice and the tumor incidence was monitored. T-cell lymphomas developed in 100 and 70% of the pim-1 transgenic mice treated with 200 and 15 mg/kg ENU, respectively. Approximately 20% of the Emu-pim-1 transgenic mice developed lymphomas after treatment with either 4, 1, or 0.1 mg/kg ENU. The nontransgenic mice developed lymphomas only after injection with 200 mg/kg (45%). The data show that Emu-pim-1 transgenic mice are approximately 25-fold more susceptible to ENU-induced lymphomagenesis than control mice. In most tumors the expression of c-myc was strongly elevated, probably as a direct or indirect effect of ENU. Analysis of the lymphomas for ras mutations revealed that approximately 10% of the lymphomas bear a ras mutation. The data indicate that at least some of these mutations are not the direct result of alkylation by ENU but rather represent spontaneous mutations that occurred later in the tumorigenic process.

Since nonrandom chromosome changes in neoplastic cells have proven to be good indicators of the site of gene alterations related to transformation, the authors examined the chromosomes of T-cell lymphomas induced in RF/J strain mice with methylnitrosourea (MNU). All treated mice developed thymic lymphomas within 10 weeks of injection. Chromosomes of the thymus cells were examined at intervals before and during lymphoma development, as well as after they were passaged in syngeneic and in nude mice for periods up to 424 days. In preparations made directly from the thymus cells nonrandom numerical and structural alterations were found that involved the X, 3, 15, 4, 8, 12, 14 and 17. (Chromosomes showing alterations are listed in decreasing order of the frequency of their occurrence). In cells passaged in nude mice the chromosomes similarly altered were the 10, X, 3, 12, 6, 1, 4, 19, 15, 18 and 14. In tumor cells passaged in syngeneic mice most of the same chromosomes were involved but the order was 15, 14, X, 1, 5, 6, 3, 11 and 12. The X, 15, 14, 3 and 12 were aberrant in both direct preparations and in those from passaged cells, suggesting that these chromosomes carry genes which, when altered, are particularly important in the multistep process of neoplastic transformation. Most of these chromosomes, or their homologs in other species, have been found to be involved frequently in several different cancers of mice and men, as for example the region on the mouse 15 carrying the Myc and Pvt-1 genes.(ABSTRACT TRUNCATED AT 250 WORDS)

N-methyl-N-nitrosourea induces murine CD4-8+ T-lymphomas that express high levels of J11d and low levels of CD5 antigens, a phenotype characteristic of immature CD4-8+ thymocytes. This assignment is supported by the fact that CD4-8+ lymphoma cell lines acquire CD4 expression after intrathymic (i.t.) transfer, a finding consistent with the established precursor potential of the normal immature CD4-8+ subset. CD4+8+ lymphomas recovered after i.t. transfer maintain a CD4+8+ phenotype in long-term culture. Northern blot analyses reveal that CD4 expression is regulated at the transcriptional level in immature CD4-8+ and CD4+8+ cell lines. CD4-8+ lymphomas express low levels of functional CD3/TCR complexes that mediate intracellular Ca2+ mobilization in response to CD3 or alpha/beta-TCR monoclonal antibody. These data suggest that the immature CD4-8+ subset contains cells capable of undergoing TCR-mediated signaling and selection events. In contrast to normal immature CD4-8+ cells, which comprise a heterogeneous and transient subset, the CD4-8+ lymphoma lines provide stable, monoclonal models of the immature CD4-8+ stage of thymocyte development.

Carbamazepine-induced lymphoproliferative disorders are relatively rare. A 32-year-old woman developed cervical lymphadenopathy while taking carbamazepine. Histologic evaluation of the lymph node biopsy specimen demonstrated near-total effacement of the nodal architecture by a population of pleomorphic immunoblasts. The predominant cell population expressed CD3, CD2, CD5, and CD4, while results of testing for CD8 were negative. On the basis of the morphologic and immunohistologic features, a diagnosis of high-grade, non-Hodgkin's lymphoma, T-cell immunoblastic type, was made. Despite the fact that aggressive behavior is usually associated with immunoblastic lymphomas, the patient has done well for 33 months after cessation of carbamazepine in the absence of chemotherapeutic treatment. The clinical features of this patient's illness, therefore, suggest that it is best regarded as a so-called pseudolymphoma.