Induction Of Thymic Lymphomas Research Articles

Kinetics of cytokine mRNA and protein expression by plastic adherent cells in the thymus after split-dose irradiation

Whole body irradiation causes significant apoptosis in various tissues such as the thymus. If apoptotic cells outnumber the phagocytic capacity of macrophages, apoptosis becomes secondary necrosis, inducing inflammatory cytokine expression in macrophages. Radiation also induces thymic lymphomas in C57BL/6 mice after four consecutive irradiations with 1.6 Gy X-rays with nearly 100% incidence. Since cancer development is modulated by a microenvironment involving macrophages, we examined the kinetics of thymocyte number and plastic adherent cell number in the thymus as well as cytokine mRNA expression by plastic adherent cells in the thymus after split-dose irradiation. Upon split-dose irradiation, thymocyte number changed dramatically, whereas plastic adherent cell number did not. Among cytokine mRNAs tested, IL-1β, IL-11 and IL-12p40 mRNAs were up regulated 2 days after the 1st and 2nd, 3rd and 4th, and 2nd and 3rd irradiations, respectively. On the other hand, TNF-α mRNA was up regulated 2 days after the 3rd irradiation and 2 weeks after the 4th irradiation. The level of IL-11 protein was also increased 2 days after 3rd and 4th irradiations. These results suggest that, upon split-dose irradiation, macrophages in the thymus produce various cytokines in a time-dependent manner, thereby contributing to induction of thymic lymphomas.

Modulating SIRT1 activity variously affects thymic lymphoma development in mice

SIRT1 is a protein deacetylase with a broad range of biological functions, many of which are known to be important in carcinogenesis, however much of the literature regarding the role of SIRT1 in cancer remains conflicting. In this study we assessed the effect of SIRT1 on the initiation and progression of thymic T cell lymphomas. We employed mouse strains in which SIRT1 activity was absent or could be reversibly modulated in conjunction with thymic lymphoma induction using either the N-nitroso-N-methylurea (NMU) carcinogenesis or the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) transgene. Decreased SIRT1 activity reduced the development of thymic lymphomas in the NMU-treated mice but was permissive for the formation of lung adenomas. Conversely, in the NPM-ALK transgenic mice, decreased SIRT1 activity had a modest promoting effect in the development of thymic lymphomas. The results of the work presented here add to the growing body of evidence that sirt1 is neither an outright oncogene nor a tumor suppressor. These opposing results in two models of the same disease suggest that the influence of sirt1 on carcinogenesis may lie in a role in tumor surveillance.

The frequency of occurrence and nature of recombinant feline leukemia viruses in the induction of multicentric lymphoma by infection of the domestic cat with FeLV-945

During feline leukemia virus (FeLV) infection in the domestic cat, viruses with a novel envelope gene arise by recombination between endogenous FeLV-related elements and the exogenous infecting species. These recombinant viruses (FeLV-B) are of uncertain disease association, but have been linked to the induction of thymic lymphoma. To assess the role of FeLV-B in the induction of multicentric lymphoma and other non-T-cell disease, the frequency of occurrence and nature of FeLV-B were examined in diseased tissues from a large collection of FeLV-infected animals. Diseased tissues were examined by Southern blot and PCR amplification to detect the presence of FeLV-B. Further analysis was performed to establish the recombination junctions and infectivity of FeLV-B in diseased tissues. The results confirmed the frequent association of FeLV-B with thymic lymphoma but showed infrequent generation, low levels and lack of infectivity of FeLV-B in non-T-cell diseases including multicentric lymphoma.

Existence of a threshold-like dose for γ-ray induction of thymic lymphomas and no susceptibility to radiation-induced solid tumors in SCID mice

Severe combined immune deficiency (SCID) mice exhibit limited repair of DNA double-strand breaks and are sensitive to ionizing radiation due to a mutation of the DNA-dependent protein kinase catalytic subunit gene. To elucidate the effects of deficient DNA double-strand break repair on radiation-induced carcinogenesis, the dose–response relationship for the induction of all tumor types was examined in wild-type and SCID mice. In wild-type mice, the incidence of thymic lymphomas at γ-ray doses up to 1 Gy was almost equal to the background level, increased gradually above 1 Gy, and reached a maximum of 12.5% at 5 Gy, which is indicative of a threshold dose of less than 1 Gy. SCID mice were extremely susceptible to the induction of spontaneous and radiation-induced thymic lymphomas. The incidence of thymic lymphomas in SCID mice irradiated with 0.1 Gy or less was similar to the background level; that is, it increased markedly from 31.7% at 0.1 Gy to 51.4% at 0.25 Gy, and reached a maximum of 80.6% at 2 Gy, suggesting the presence of a threshold-like dose at low γ-ray doses, even in radiosensitive SCID mice. As the average latency for the induction of thymic lymphomas at 0.1 Gy was significantly shortened, the effect of 0.1 Gy γ-rays on thymic lymphoma induction was marginal. The high susceptibility of SCID mice to develop thymic lymphomas indicates that thymic lymphomas are induced by a defect in DNA double-strand break repair or V(D)J recombination. Excessive development of tumors other than thymic and nonthymic lymphomas was not observed in SCID mice. Furthermore, our data suggest that the defective double-strand break repair in SCID mice is not a major determinant for the induction of nonlymphoid tumors.

Suppression of Thymic Lymphoma Induction by Life-Long Low-Dose-Rate Irradiation Accompanied by Immune Activation in C57BL/6 Mice

The induction of thymic lymphomas by whole-body X irradiation with four doses of 1.8 Gy (total dose: 7.2 Gy) in C57BL/6 mice was suppressed from a high frequency (90%) to 63% by preirradiation with 0.075 Gy X rays given 6 h before each 1.8-Gy irradiation. This level was further suppressed to 43% by continuous whole-body irradiation with 137Cs gamma rays at a low dose rate of 1.2 mGy/h for 450 days, starting 35 days before the challenging irradiation. Continuous irradiation at 1.2 mGy/h resulting in a total dose of 7.2 Gy over 258 days yielded no thymic lymphomas, indicating that this low-dose-rate radiation does not induce these tumors. Further continuous irradiation up to 450 days (total dose: 12.6 Gy) produced no tumors. Continuously irradiated mice showed no loss of hair and a greater body weight than unirradiated controls. Immune activities of the mice, as measured by the numbers of CD4+ T cells, CD40+ B cells, and antibody-producing cells in the spleen after immunization with sheep red blood cells, were significantly increased by continuous 1.2-mGy/h irradiation alone. These results indicate the presence of an adaptive response in tumor induction, the involvement of radiation-induced immune activation in tumor suppression, and a large dose and dose-rate effectiveness factor (DDREF) for tumor induction with extremely low-dose-rate radiation.

The D5Mit7 locus on mouse chromosome 5 provides resistance to gamma-ray-induced but not N-methyl-N-nitrosourea-induced thymic lymphomas.

Susceptibility to gamma-ray induction of thymic lymphomas in mouse strains is controlled by low-penetrance genetic variant alleles. Our previous genome-wide scan of a mouse backcross between BALB/c and MSM strains suggested the existence of a BALB/c resistance locus near D5Mit5 on chromosome 5. To confirm this resistance, we produced congenic mice carrying a 28.4 cM region between D5Mit4 and D5Mit315 from the MSM parental strain on the BALB/c background. Lymphomas were induced in their progeny by gamma-ray irradiation or administration of N-methyl-N-nitrosourea (MNU), an alkylating agent. The incidence of radiogenic lymphomas was 87.5% in mice of the M/M genotype at D5Mit7, significantly higher than the 46% incidence in mice of the C/M genotype, indicating highly significant linkage between the locus and the resistance (P = 0.000054). In contrast, the frequencies of MNU-induced thymic lymphomas were similar between the two genotypes (P = 0.35 in chi2 test). These results confirm the presence of a resistance allele for gamma-ray induction of thymic lymphomas near the D5Mit7 locus and strongly suggest that this locus modifies carcinogenic risk from exposure to radiation but not to alkylating agents.

Radiation-induced-thymic lymphoma occurs in young, but not in old mice

Young mice exposed to fractionated whole-body irradiation develop thymic lymphoma. By using young and old mice, we examined the effect of age on the occurrence of radiation-induced thymic lymphoma in mice. In the first experiment, young and old mice were grafted with newborn thymus under kidney capsule and then treated with fractionated whole-body irradiation (FWI). In the second and third experiments, four combinations of bone marrow chimeras were constructed by transplanting bone marrow cells from young and old mice into young and old mice. Then these chimera mice were grafted with newborn thymus and treated with fractionated whole-body irradiation. The results in the present study indicate that the incidence of thymic lymphoma is influenced by age factors of thymic microenvironment, bone marrow, and host environment. If they are all young, the incidence of thymic lymphoma is high. If one of these is old, the incidence definitely decreases. Thymic lymphoma never occurred in old thymic environment even in the presence of young thymocytes. In conclusion, age advantage is present in the induction of thymic lymphoma after the treatment with FWI and the incidence definitely decreases in the presence of old factors.

Combined Effect of X-rays and N-Ethyl-N-Nitrosourea at Threshold Dose on The Induction of Thymic Lymphomas in B6C3F1 Mice

Combined Effect of X-rays and N-Ethyl-N-Nitrosourea at Threshold Dose on The Induction of Thymic Lymphomas in B6C3F1 Mice

Dose-response Relationship of Thymic Lymphoma Induction by Gamma Radiation and Induction of Non-thymic Lymphomas at Very Low Doses in SCID Mice

Dose-response Relationship of Thymic Lymphoma Induction by Gamma Radiation and Induction of Non-thymic Lymphomas at Very Low Doses in SCID Mice

Development and molecular analysis of thymic lymphomas induced by ionizing radiation in Scid mice

The Scid mouse is well known to be immunodeficient and also radiosensitive because of point mutation in the DNA-dependent protein kinase catalytic subunits (DNA-PKcs) gene. To analyze the effects of Scid mutation on radiation carcinogenesis, Scid ( Scid homozygote), C.B-17 (wild-type) and their (C.B-17×Scid) F1 hybrid ( Scid heterozygote) were used. These strains of mice were first examined for acute effects, and then irradiated with 1–3 Gy gamma rays for carcinogenesis experiments. Scid mice are extremely susceptible to the induction of thymic lymphomas by ionizing radiation. Molecular analyses demonstrated that mutation of the Ras gene contributed less to the induction of thymic lymphomas, although Notch1 mutation played a role. These results suggest a close relationship between radiosensitivity and the development of thymic lymphomas in Scid mice, and correlation of reduced DNA-PK activity with an increase in the yield of deletions or insertions in oncogene(s) rather than point mutations.

Tlag2, an N-methyl-N-nitrosourea susceptibility locus, maps to mouse chromosome 4

Susceptibility to N-methyl-N-nitrosourea (MNU)–induced lymphomas is a multigenic trait. We previously mapped a resistance locus (Tlag1) to mouse chromosome 7 in genetic crosses of sensitive AKR with resistant C57L mice. Analysis of the MNU sensitivity of AKXL recombinant inbred strains that are homozygous for the AKR allele of Tlag1 suggested that at least two additional tumor susceptibility loci segregate in these crosses. A second susceptibility locus (Tlag2) now has been mapped to chromosome 4. Only those mice that inherited the susceptibility alleles at both Tlag1 and Tlag2 were sensitive to MNU induction of thymic lymphomas, suggesting that these two loci interact. Chromosome 4 has been associated with susceptibility to hematopoietic tumor development in several mouse models, suggesting that one or more genes mapping to this chromosome are important in lymphomagenesis in general. © 2002 Wiley-Liss, Inc.

Tlag2, an N‐methyl‐N‐nitrosourea susceptibility locus, maps to mouse chromosome 4

Susceptibility to N-methyl-N-nitrosourea (MNU)-induced lymphomas is a multigenic trait. We previously mapped a resistance locus (Tlag1) to mouse chromosome 7 in genetic crosses of sensitive AKR with resistant C57L mice. Analysis of the MNU sensitivity of AKXL recombinant inbred strains that are homozygous for the AKR allele of Tlag1 suggested that at least two additional tumor susceptibility loci segregate in these crosses. A second susceptibility locus (Tlag2) now has been mapped to chromosome 4. Only those mice that inherited the susceptibility alleles at both Tlag1 and Tlag2 were sensitive to MNU induction of thymic lymphomas, suggesting that these two loci interact. Chromosome 4 has been associated with susceptibility to hematopoietic tumor development in several mouse models, suggesting that one or more genes mapping to this chromosome are important in lymphomagenesis in general.

P53-Deficiency directly revealed the non-threshold leukemogenesis by a single administration of relatively low-dose of methyl nitrosourea

Quantitative increase in chemically induced leukemogenic sensitivity was seen in p53 deficient bone marrow (BM) cells, which was utilized to resolve the non-threshold issue directly. Methods: Because of induction of thymic lymphoma at a high frequency in the p53 K.O. mice, the transplantation assay (Hirabayashi, et al., 1997) was employed to focus on the hemopoietic system solely as a target tissue. Recipient mice were lethally irradiated and repopulated with either p53 deficient or wild BM cells. A graded doses of MNU by which incidence of hemopoietic neoplasms is less than 10% in the wild type were treated, i.p., to the recipients one month later when repopulation was completed. Results: All the mice repopulated by p53-deficient (p53−/−) BM and treated with over 14.8 mg/kg.bw died from hemopoietic malignancies by 100 days after the treatment, which was higher and faster than groups repopulated with p53+/− or wild type BM. In the group of p53−/−, including the 6.6 mg/kg-bw group, the days at the 50% incidence in hemopoietic neoplasms plotted showed a linear regression line, although those in the other groups, p53+/− and P53+/+, vanished on the middle of their own regression lines. The result clearly suggests, on one hand, that the extrapolation lines indicated were the non-threshold probabilistic appearance of neoplasms not only in heterozygous but also in the wild animals. However, because of DNA-repair and other molecular protection mechanism available in an intact animal, present study still can not answer the question whether a threshold might show up into a range of observation when experimental animals as a denominator could be increased infinitely in the wild type experimental animals.

Different cellular basis for the resistance of C3H and STS strain mice to the development of thymic lymphomas following fractionated whole-body irradiation: Analysis using radiation bone marrow chimeras

Purpose : B10 strain mice are susceptible to the induction of thymic lymphomas by fractionated whole-body X-irradiation (FI), whereas C3H and STS mice are resistant. The nature of the factors responsible for the strain difference in the susceptibility to thymic lymphomagenesis was investigated by using radiation bone marrow chimeras. Methods : Radiation bone marrow chimeras were constructed in the reciprocal donor-host combinations of susceptible and resistant mice with use of Thy 1 markers that allow the genetic origins of thymocytes and thymic lymphomas to be determined. Results : B10.Thy 1.1 →C3H, B10.Thy 1.1 →STS as well as B10.Thy 1.1 →B10 bone marrow chimeras manifested a high incidence of thymic lymphomas after FI-treatment, whereas C3H.Thy 1.1 →B10 and STS →B10.Thy →1.1 as well as C3H.Thy 1.1 →C3H and STS →STS chimeras manifested a low incidence of thymic lymphoma. Furthermore, FI-treatment of (B10.Thy 1.1 + C3H) →B10.Thy 1.1 mixed chimeras resulted in the generation of similar numbers of thymic lymphomas of B10 and C3H origins, whereas FI-treatment of (B10.Thy 1.1+ STS) →B10.Thy 1.1 mixed chimeras preferentially induced thymic lymphomas of B10 origin. Conclusions : (1) genetic factors responsible for the strain-dependent susceptibility and/or resistance to FI-induced lymphomagenesis exert their effects entirely on bone-marrow derived cells, (2) host environments of C3H and STS resistant mice are not inhibitory for the development of thymic lymphomas and (3) the resistance of STS mice to FI-induced thymic lymphomagenesis is an intrinsic property of thymocytes, whereas C3H and B10 thymocytes themselves are similarly susceptible for FI-induced thymic lymphomagenesis.

Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis.

Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontaneous thymic lymphomas and sarcomas. We have previously shown that PMS2(-/-) mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methyl-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O(6)-methylguanine (O(6)-mG), which, if unrepaired by O(6)-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O(6)-mG:T mismatches in MMR deficient cells. Tumor induction is less in MMR(+/+) mice because cells with residual DNA adducts die, whereas mutagenized cells survive in MMR(-/-) mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase-MGMT-gene) is known to block MNU induced tumorigenesis in mice with functional MMR. To further determine the sensitivity of PMS2(-/-) mice to MNU and the protective effect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS2(-/-) mice and PMS2(-/-)/hMGMT(+) mice. No thymic lymphomas were found in MNU-treated PMS2(+/+) and PMS2(+/-) mice. At 1 year, 46% of the MNU-treated PMS2(-/-) mice developed thymic lymphoma, compared with an incidence of 25% in both untreated PMS2(-/-) mice and MNU treated PMS2(-/-)/hMGMT(+) mice. In addition, a significantly shorter latency in the onset of thymic lymphomas was seen in MNU-treated PMS2(-/-) mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2(-/-) and PMS2(-/-)/hMGMT(+) mice, but not in the spontaneous lymphomas. These data suggest that PMS(-/-) mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways.

Low Frequency of Ras Gene Mutation in Spontaneous and Gamma-Ray-Induced Thymic Lymphomas of Scid Mice

Scid mice, which have a defect in the capacity to repair DNA double-strand breaks, were highly prone to the induction of thymic lymphomas after exposure to ionizing radiation; approximately 70% of mice developed lymphomas within 1 year after exposure to 1-3 Gy, whereas approximately 20% of unirradiated control mice developed lymphomas. To gain information on the possible role of Ras activation in development of thymic lymphomas in scid mice, we have examined both the frequency and the spectrum of Kras and Nras mutations in spontaneous and radiation-induced lymphomas. Neither activated Kras nor Nras genes were detected in spontaneous lymphomas, while Kras mutations increased in a dose-dependent manner in radiation-induced lymphomas. However, Kras mutations were infrequent (6% in lymphomas in mice exposed to 1 Gy, 12.5% in those exposed to 2 Gy, 16.7% in those exposed to 3 Gy), and no mutations were detected in Nras genes, suggesting that Ras mutation was not significantly involved in the development of thymic lymphomas in scid mice. Analysis of the spectrum of Kras mutations demonstrated unique mutations in both codons 13 (GGC to GAC) and 61 (CAA to CTA) in addition to the commonly identified substitution of GAT for GGT in codon 12 of Kras.

The adaptive response in radiobiology: evolving insights and implications.

The first of the regularly reproducible experiments to show that very low doses of ionizing radiation, like very low doses of chemical agents, could induce mechanisms whereby cells become better fit to cope with subsequent exposures to high doses were carried out on the induction of chromosome aberrations in cultures of human lymphocytes. If cells that had been exposed to a very low dose (1 cGy) of X rays were subsequently exposed to a relatively high dose (1 Gy), approximately half as many chromosome breaks were induced. Subsequent experiments showed that this adaptive response to low doses requires a certain minimal dose before it becomes active; occurs only within a relatively small window of dose; is dose-rate dependent; and depends on the genetic constitution of the people or animals exposed, with some being unresponsive. It was further shown that the response to the low-dose preexposure was not instantaneous but took approximately 4 to 6 hr to become fully active, and could be prevented if during this period protein synthesis was inhibited, i.e., a necessary protein (enzyme) was being induced. In fact, subsequent experiments with two-dimensional gel electrophoresis showed new proteins in cells irradiated with 1 to 2 cGy. The adaptation induced by low doses of radiation was therefore attributed to the induction of a novel efficient chromosome break repair mechanism that if active at the time of challenge with high doses would lead to less residual damage. This hypothesis was strengthened by a series of experiments in which it was found that inhibitors of poly(ADP-ribose)polymerase, an enzyme implicated in DNA strand break rejoining, could prevent the adaptive response. Although the phenomenon is well established in cellular systems, it is still problematical as to whether or not it will have any utility in establishing risks of ionizing radiation to humans. Newer experiments have now been carried out on the mechanisms underlying the effect and whether or not the effect can manifest itself as a decrease in the number of induced cancers and radiation-induced mortality. Experiments with restriction enzymes now indicate that double-strand breaks in DNA can be triggering events in adaptation. In addition, preliminary experiments on the survival of whole-body irradiated mice have shown that multiple exposures to low adapting doses can have profound effects on survival, and other experiments have shown that adaptation can affect the induction of thymic lymphoma in irradiated mice. It therefore appears that the initial experiments behind the adaptive response have led to a vigorous worldwide effort to understand the basic mechanisms behind it. This effort is stimulated both by a desire to understand the basic cell biology behind the response and a desire to see if indeed this phenomenon affects the estimation of risks of low-level radiation exposure.

Induction of Thymic Lymphoma in Mice Administered the Dideoxynucleoside ddC

Induction of Thymic Lymphoma in Mice Administered the Dideoxynucleoside ddC. Sanders, V. M., Elwell, M. R., Heath, J. E., Collins, B, J., Dunnick, J. K., Rao, G. N., Prejean, D., Lindamood, C., III, and Irwin, R. D. (1995). Fundam. Appl. Toxicol. 27, 263-269. Groups of 10 male and 20 female B6C3F1 mice received 0, 500, or 1000 mg/kg/day 2′,3′-dideoxycytidine (ddC) by gavage for 13 weeks. At the end of the 13-week exposure period all males and 10 females per group were necropsied while the remaining females were held for 1 month without further treatment, Thymic atrophy was present at the 13-week necropsy in male and female mice administered 1000 mg/kg/day and in females administered 500 mg/kg/day, but was not present in females following 1 month of recovery. Thymic lymphoma was present in 1 female that received 500 mg/kg/day and 1 female that received 1000 mg/kg/day. In a follow-up study groups of 70 female mice received 0, 500, or 1000 mg/kg/day for 13 weeks. At the end of the 13-week exposure period 20 mice per group were necropsied and the remaining animals held for 3 months without further treatment. Thymic atrophy was observed in ddC-exposed groups at the 13-week necropsy but not in mice allowed to recover for 13 weeks. Thymic lymphoma occurred in 3150 mice that received 500 mg/kg/day and in 17150 mice that received 1000 mg/kg/day but did not occur in mice from the vehicle control group.

Induction of Thymic Lymphoma in Mice Administered the Dideoxynucleoside ddC

Groups of 10 male and 20 female B6C3F1 mice received 0, 500, or 1000 mg/kg/day 2′,3′-dideoxycytidine (ddC) by gavage for 13 weeks. At the end of the 13-week exposure period all males and 10 females per group were necropsied while the remaining females were held for 1 month without further treatment. Thymic atrophy was present at the 13-week necropsy in male and female mice administered 1000 mg/kg/day and in females administered 500 mg/kg/day, but was not present in females following 1 month of recovery. Thymic lymphoma was present in 1 female that received 500 mg/kg/day and 1 female that received 1000 mg/kg/day. In a follow-up study groups of 70 female mice received 0, 500, or 1000 mg/kg/day for 13 weeks. At the end of the 13-week exposure period 20 mice per group were necropsied and the remaining animals held for 3 months without further treatment. Thymic atrophy was observed in ddC-exposed groups at the 13-week necropsy but not in mice allowed to recover for 13 weeks. Thymic lymphoma occurred in 3/50 mice that received 500 mg/kg/day and in 17/50 mice that received 1000 mg/kg/day but did not occur in mice from the Vehicle Control group.

Unexpected effects of the severe combined immunodeficiency mutation on murine lymphomagenesis.

Strain C.B17 scid/scid (SCID) mice, which lack functional T and B lymphocytes, show heightened susceptibility to the induction of thymic lymphomas by x-irradiation. Susceptibility is highest in thymus-chimeric SCID-BL mice (thymectomized SCID mice bearing a C57BL thymus graft). All SCID-BL lymphomas originate in the cells of the thymic graft (C57BL type) and lack murine leukemia virus expression. Both SCID and SCID-BL lymphomas are phenotypically CD4-8+ and/or CD4+8+, but only the SCID-BL tumors express CD3. Injection of C57BL or BALB/c bone marrow into irradiated SCID-BL mice prevents lymphoma development, but SCID marrow is completely ineffective. The results suggest that the scid condition enhances the activity of a putative lymphomagenic agent induced in the bone marrow by x-irradiation and that C57BL thymic cells are highly sensitive targets. Moreover, the failure of SCID bone marrow to protect against lymphomagenesis vs. the efficacy of marrow from immunocompetent donors points to involvement of T or B lineage cells in this process.