Bone Marrow-Thymus Interactions during Thymic Lymphomagenesis Induced by Fractionated Radiation Exposure in B10 Mice: Analysis Using Bone Marrow Transplantation between Thy 1 Congenic Mice

Sado, Toshihiko; Kamisaku, Hitoko; Kubo, Eiko

doi:10.1269/jrr.32.supplement2_168

Cited by 36 publications

(39 citation statements)

References 16 publications

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“…24) Classical studies of radiation induction of mouse thymic lymphomas demonstrated that fractionated whole-body irradiation causes thymic atrophy and depletion of bone marrow cells, which lead to regeneration and differentiation arrest of thymocytes surviving the exposure. [6][7][8][25][26][27] Interestingly, the lymphomagenesis is suppressed by bone marrow transplantation. 7,8,[25][26][27][28] Potworowski et al 29) reported that dendritic cells, but not thymocyte precursors, supplied by bone marrow to the thymus play a key role in the prevention of lymphoma development.…”

Section: Discussionmentioning

confidence: 99%

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ‐ray‐induced and N‐methyl‐N‐nitrosourea‐induced thymic lymphomas

Sato¹,

Tamura²,

Ochiai³

et al. 2003

Cancer Science

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Low-penetrance genes control different susceptibilities to γ γ γ γ-rayinduced thymic lymphomas in mouse strains. Our previous genetic analyses with backcross mice between BALB/c and MSM strains and congenic lines localized one such gene near the D4Mit12 locus on chromosome 4. N-Methyl-N-nitrosourea (MNU) is a guanine base-alkylating agent and differs from γ γ γ γ-radiation in its mechanism of mutagenic action. Accordingly, in this study, we examined whether or not the locus also provides susceptibility to MNU-induced thymic lymphomas using 84 offsprings derived from congenic mice for D4Mit12. Association analysis provided a suggestive linkage at D4Mit12 (P = = = =0.0075) and the linkage was sustained by the peak of likelihood ratio statistical values being at the same position as that for the γ γ γ γ-ray-induced lymphomas. The results strongly suggest that the BALB/c allele near D4Mit12 is associated with susceptibility to lymphomas induced by two carcinogenic agents having different mechanisms of mutagenic action. (Cancer Sci 2003; 94: 668-671) enetic variation plays a key role in determining the range of individual susceptibility to cancers within human population, and there is increasing evidence that a high proportion of cancers arise in a susceptible subpopulation that carries lowpenetrance genes. [1][2][3][4][5] The importance of susceptibility genes has been underlined, because the identification of such genes has possible public health implications, and can be achieved using information from the human genome project. Mouse thymic lymphomas are one of the classical models of radiation-induced and chemical carcinogen-induced malignancies, [6][7][8] and the model involves low-penetrance susceptibility genes in mouse strains. For instance, BALB/c (C) is susceptible to the development of γ-ray-induced thymic lymphomas 9, 10) while MSM (M), an inbred strain derived from Japanese wild mice, Mus musculus molossinus, shows resistance. 11) Our previous analyses of backcross mice between sensitive and resistant strains and congenic lines localized one of the susceptibility genes near the D4Mit12 locus on chromosome 4. 12) Mice with the C/M genotype at D4Mit12 showed an incidence twice as high as that in mice with the M/M genotype. This indicated that the BALB/c allele near D4Mit12 provides susceptibility in a dominant manner, although the nature of the susceptibility locus is not clear.N-Methyl-N-nitrosourea (MNU) is an alkylating agent that can modify guanine bases in DNA and some of the modified guanines are changed to adenine after DNA replication. The mode of action differs from that of radiation; i.e., the major type of radiation-induced DNA change is large mutations, such as deletion and translocation.13) It is of interest, therefore, to know whether or not the BALB/c allele near the D4Mit12 locus provides susceptibility to MNU-induced thymic lymphomas as well. This may give a clue to the function of the susceptibility gene in lymphomagenesis. In this study we have investigated this issue using congenic mice ...

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Section: Discussionmentioning

confidence: 99%

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ‐ray‐induced and N‐methyl‐N‐nitrosourea‐induced thymic lymphomas

Sato¹,

Tamura²,

Ochiai³

et al. 2003

Cancer Science

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“…Alternatively, radiation might cause (epi)genetic changes in an oncogene or tumor suppressor gene in surviving thymocytes with a Notch1 deletion during forced proliferation after irradiation. Such a situation would be created by thymocyte depletion because of thymocyte death in the thymus and a radiation-induced shortage in the supply of pre-T cells to the thymus (51). Transplantation of the thymocytes surviving after irradiation into thymuses of lethally irradiated mice revealed the presence and the induction of prelymphoma T cells in the irradiated thymocyte population, which can proliferate abnormally to additionally evolve into fully autonomous thymic lymphomas in thymus (51)(52)(53).…”

Section: Deletions Ofmentioning

confidence: 99%

“…Such a situation would be created by thymocyte depletion because of thymocyte death in the thymus and a radiation-induced shortage in the supply of pre-T cells to the thymus (51). Transplantation of the thymocytes surviving after irradiation into thymuses of lethally irradiated mice revealed the presence and the induction of prelymphoma T cells in the irradiated thymocyte population, which can proliferate abnormally to additionally evolve into fully autonomous thymic lymphomas in thymus (51)(52)(53). Prelymphoma cells compose 5.2 ϫ 10 -6 % of thymocytes on the 14th day after irradiation (52).…”

Section: Deletions Ofmentioning

confidence: 99%

Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of theNotch1Gene in Mouse Thymic Lymphomas

et al. 2004

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Deregulated V(D)J recombination-mediated chromosomal rearrangements are implicated in the etiology of B-and T-cell lymphomagenesis. We describe three pathways for the formation of 5-deletions of the Notch1 gene in thymic lymphomas of wild-type or V(D)J recombination-defective severe combined immune deficiency (scid) mice. A pair of recombination signal sequence-like sequences composed of heptamer-and nonamer-like motifs separated by 12-or 23-bp spacers (12-and 23-recombination signal sequence) were present in the vicinity of the deletion breakpoints in wild-type thymic lymphomas, accompanied by palindromic or nontemplated nucleotides at the junctions. In scid thymic lymphomas, the deletions at the recombination signal sequence-like sequences occurred at a significantly lower frequency than in wild-type mice, whereas the deletions did not occur in Rag2 ؊/؊ thymocytes. These results show that the 5-deletions are formed by Rag-mediated V(D)J recombination machinery at cryptic recombination signal sequences in the Notch1 locus. In contrast, one third of the deletions in radiation-induced scid thymic lymphomas had microhomology at both ends, indicating that in the absence of DNAdependent protein kinase-dependent nonhomologous end-joining, the microhomology-mediated nonhomologous end-joining pathway functions as the main mechanism to produce deletions. Furthermore, the deletions were induced via a coupled pathway between Rag-mediated cleavage at a cryptic recombination signal sequence and microhomology-mediated endjoining in radiation-induced scid thymic lymphomas. As the deletions at cryptic recombination signal sequences occur spontaneously, microhomology-mediated pathways might participate mainly in radiation-induced lymphomagenesis. Recombination signal sequence-mediated deletions were present clonally in the thymocyte population, suggesting that thymocytes with a 5-deletion of the Notch1 gene have a growth advantage and are involved in lymphomagenesis.

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“…Thus, atrophic thymus may constitute a microenvironment that allows damaged thymocytes to find a population of proliferating and precancerous cells. Indeed, it was reported that prelymphoma cells develop in atrophic thymus within 2 weeks after irradiation (Muto et al, 1987;Sado et al, 1991). However, study of genetic changes of thymocytes in the atrophic thymus has not been performed.…”

Section: Introductionmentioning

confidence: 99%

Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation

et al. 2007

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Whole-body c-irradiation to mice causes thymic atrophy where a population of precancerous cells with mutation can be found. Thus, clonal growth and DNA changes at Bcl11b, Ikaros, Pten, Notch1 and Myc were examined in not only thymic lymphomas but also in atrophic thymuses at various times after irradiation. Clonal expansion was detected from the distinct patterns of rearrangements at the TCRb receptor locus in a fraction of atrophic thymuses at as early as 30 days after irradiation. This expansion may be in part owing to the rearranged TCRb signaling because the transfer of bone marrow cells with the rearrangement and the wild-type locus into severecombined immunodeficiency mice showed preferential growth of the rearranged thymocytes in atrophic thymus. Loss of heterozygosity (LOH) at Bcl11b and trisomy of Myc were found at high frequencies in both lymphomas and atrophic thymuses, and in contrast, LOH at Ikaros and Pten were rare in atrophic thymuses but prevalent in lymphomas. Notch1 activation was detected in lymphomas and in atrophic thymuses only at a late stage. Similar patterns of DNA changes were found in atrophic thymuses induced in Bcl11b þ /À mice. These results suggest the order of genetic changes during lymphomagenesis, Bcl11b and Myc being at the early stage; whereas Ikaros, Pten and Notch1 at the late stage.

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Bone Marrow-Thymus Interactions during Thymic Lymphomagenesis Induced by Fractionated Radiation Exposure in B10 Mice: Analysis Using Bone Marrow Transplantation between Thy 1 Congenic Mice

Cited by 36 publications

References 16 publications

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ‐ray‐induced and N‐methyl‐N‐nitrosourea‐induced thymic lymphomas

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ‐ray‐induced and N‐methyl‐N‐nitrosourea‐induced thymic lymphomas

Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of theNotch1Gene in Mouse Thymic Lymphomas

Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation

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