Expression of LECAM-1 and LFA-1 on PRE-B lymphoma cells but not on preneoplastic pre-B cells in SL/Kh mice

Activation-induced cytidine deaminase (AID), which is essential to both class switch recombination and somatic hypermutation of the Ig gene, is expressed in many types of human B cell lymphoma/ leukemia. AID is a potent mutator because it is involved in DNA breakage not only of Ig but also of other genes, including protooncogenes. Recent studies suggest that AID is required for chromosomal translocation involving cmyc and Ig loci. However, it is unclear whether AID plays other roles in tumorigenesis. We examined the effect of AID deficiency on the generation of surface Ig-positive B cell lymphomas in Emu-cmyc transgenic mice. Almost all lymphomas that developed in AID-deficient transgenic mice were pre-B cell lymphomas, whereas control transgenic mice had predominantly B cell lymphomas, indicating that AID is required for development of B but not pre-B cell lymphomas from cmyc overexpressing tumor progenitors. Thus, AID may play multiple roles in B cell lymphomagenesis.somatic hypermutation ͉ Pim1 ͉ secondary hit ͉ clonal expansion S omatic hypermutation (SHM) originally was considered to take place specifically in the IgV genes (1). Subsequently, several genes other than those encoding Igs were shown to be targets of SHM in activated B cells and human B cell lymphomas. Such target genes include MYC, IG alpha, PAX5, BCL6, and PIM1 (2-4). Activation-induced cytidine deaminase (AID) has been shown to be essential for SHM, gene conversion, and class switch recombination (CSR), three types of genetic alteration induced by antigen stimulation of B lymphocytes (5-9).Original studies on human lymphomas indicated that AID is expressed in B cell lymphomas of germinal center (GC) origin, such as diffuse large B cell lymphoma, Burkitt's lymphoma, and follicular lymphoma, where AID is expressed physiologically (3, 10, 11). However, more recent analyses have extended AID expression to other types of human B cell lymphoma, including chronic lymphocytic leukemia, Hodgkin's lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma, mediastinal B cell lymphoma, hairy cell leukemia, and acute lymphocytic leukemia (12-16). The results of these studies suggest that AID may be involved in the pathogenesis of human B cell malignancy, including not only GC-derived B cell lymphoma but also almost all other types of human B cell lymphoma.Studies on AID transgenic (Tg) animals have revealed that all individual mice develop T cell lymphomas in which genes for non-Igs such as T cell receptor (tcr), cmyc, pim1, cd4, and cd5 accumulate massive mutations in the region 3Ј proximal to each promoter (17, 18). The AID Tg mice also develop B cell lymphoma, albeit much less frequently (I-m.O. and T.H., unpublished data). Studies also report AID to be essential for the mouse chromosomal translocation T(12;15), which corresponds to the human chromosomal translocation t(8;14), the hallmark of endemic Burkitt's lymphoma, in IL-6 Tg mice (19,20). However, these animals did not develop plasmacytoma; instead, they developed polyclonal ade...

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“…The pre-B and B cell lymphomas were defined in this report by B220 (26)(27)(28). The B cell lymphomas expressed IgM, IgG, or IgA.…”

Section: Resultsmentioning

confidence: 99%

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

Kotani¹,

Kakazu

Tsuruyama

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…4A), as in most SL/Kh lymphomas. 3,18,19) We compared the phenotype of lymphomas with the integration in Svi1 (the second intron of Stat5a) and in Svi3. As previously shown, Svi1 lymphomas had elevated c-myc expression, since c-myc is one of the downstream transcription targets of stat5a.…”

Section: Resultsmentioning

confidence: 99%

“…The SL/Kh mice show transient expansion of pre-B cells in bone marrow at 3-6 weeks of age in advance of lymphoma development. 3,18,19) Such an expansion is not caused by MuLV 18,29,30) but by a semi-dominant SL/Kh allele at Bomb1 on chromosome 3.…”

Section: Discussionmentioning

confidence: 99%

Svi3: A provirus common integration site in c‐myc in SL/Kh pre‐B lymphomas

et al. 2003

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t has been shown that retroviral insertions in host DNA may cause hematopoietic malignancies by enhancing the expression of a proto-oncogene or by disrupting tumor suppressor genes at the integration sites.1) Recent progress in the technique of retrotransposon tagging has greatly facilitated the identification of cancer-related genes.2) SL/Kh, a pre-B lymphoma-prone inbred mouse strain, provides a unique model to investigate the host genetic and epigenetic factors determining susceptibility and types of disease. 3)Mice of this strain develop spontaneous pre-B lymphomas at >90% incidence by 6 months of age. 4) Several lines of evidence indicate that the endogenous murine leukemia virus (MuLV) plays an etiologic role in the genesis of SL/Kh lymphoma. 5-7)Somatically acquired proviruses are frequently observed in the genomic DNAs of lymphomas. 6) By applying inverse polymerase chain reaction (IPCR), we have identified a number of virus integration hot spots in SL/Kh lymphoma DNA; we have named them SL/Kh virus integration sites (Svi) and numbered them serially in the order of discovery. 7) Svi3 is one of them, in which 3 out of 60 SL/Kh lymphomas had clonal integration of a provirus of the ecotropic MuLV within the promoter region and the first exon of the c-myc. The c-myc encodes a transcription factor that is a cellular homologue of the viral transforming gene encoded by the avian myelocytomatosis virus MC29. 8)Leukemias and lymphomas induced by retroviruses frequently have integration in or near the c-myc gene, 9,10) suggesting that these tumors are clonal or semi-clonal outgrowths of cells that acquired a selective growth advantage in vivo as a consequence of c-myc insertions. In this report, we will describe the provirus integrations at Svi3 and their biological effects in SL/Kh mouse lymphomagenesis. Materials and MethodsMouse strain. SL/Kh is an inbred mouse strain maintained in

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“…FACS analysis Surface phenotypes of lymphomas were analyzed by flow cytometry using a FACScan (Becton Dickinson, Mountain View, CA) as described previously. 12) The following monoclonal antibodies were used: fluorescein isothiocyanate (FITC)-coupled CD3, CD8, CD16, Mac-1 and IgM, PE-coupled NK1.1, B220, CD4 and CD5; Thy1.1 was stained indirectly with a second antibody, FITC-labeled anti mouse IgG 2a . To block Fc receptor, unlabeled CD16 antibody was used at a concentration of 0.1 mg/ml, at which staining of FITC-labeled anti-CD16 was totally abolished in a preliminary competition assay.…”

Section: Methodsmentioning

confidence: 99%

Mixed Phenotype Lymphomas in Thymectomized (SL/KhxAKR/Ms)F1 Mice

Лу

Hayashi

1999

Japanese Journal of Cancer Research

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Lymphomagenesis in mice is determined both by genetic and epigenetic mechanisms. The inbred strain SL/Kh mice selectively develop pre‐B lymphomas and AKR/Ms, T‐lymphomas. In crosses between SL/Kh and AKR/Ms, an AKR‐derived dominant gene Tlsm1 (Thymic lymphoma susceptible mouse‐1) determines the type of lymphoma to be a T‐lymphoma. As an approach to the role of Tlsm1, we studied the effect of thymectomy at 1 week of age in (SL/KhxAKR/Ms)Fl hybrids. In intact F1 mice, the predominant type of lymphoma was of T‐lineage, whereas in thymectomized mice, it was an unusual mixed‐phenotype lymphoma. They were basically CD5+ B‐lymphomas with a rearranged immunoglobulin gene, but carried NK1 and Mac1 on the cell surface and large lysosomal granules in the cytoplasm. Histologically, the lymphoma consisted of large lymphoblastoid cells and infiltrated the spleen, lymph node and liver. Electron microscopy and histochemistry revealed numerous cytoplasmic granules containing acid phosphatase and lysozyme. These morphological features are suggestive of large granular lymphocytes. They expressed interleukin‐4, perforin, and interferon‐γ. On transplantation, these lymphoma cells grew equally well in intact and thymectomized F1 recipients.

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Expression of LECAM-1 and LFA-1 on PRE-B lymphoma cells but not on preneoplastic pre-B cells in SL/Kh mice

Cited by 7 publications

References 15 publications

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

Svi3: A provirus common integration site in c‐myc in SL/Kh pre‐B lymphomas

Mixed Phenotype Lymphomas in Thymectomized (SL/KhxAKR/Ms)F1 Mice

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