Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma.

McGuire, Elizabeth A.; Rintoul, C E; Sclar, G M; Korsmeyer, Stanley J.

doi:10.1128/mcb.12.9.4186

Cited by 106 publications

(91 citation statements)

References 61 publications

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“…Comparing groups to the 7/+, LMO1 mice, the incidence of thymic lymphomas was signi®cantly reduced in each of the three groups (P50.02) and the latency was longer in the +/+, double transgenics (P50.05) but not in the other groups (Table 1). As previously reported, the spontaneous incidence of lymphomas in LMO1+ mice was about 30% with a mean latency of 250 days (from the treatment date of 42 days), whereas for normal mice it was less than 3% at one year (McGuire et al, 1992;Dumenco et al, 1993).…”

Section: Mnu-induced Lymphomas In Lmo1 and Mgmt+ Transgenic Micesupporting

confidence: 77%

“…As can be seen in Figure 1, the incidence was highest in the LMO1 only group (7/ +), in which 29/32 (90.6%) mice developed lymphoma with a median latency of 137 days post MNU treatment (range 80 ± 365 days). In this oncogene initiated mouse, MNU acts as a tumor`initiating' and`promoting' agent, increasing the incidence and decreasing the latency of tumors associated with expression of LMO1 ( Figure 1) compared to the spontaneous incidence of lymphomas in these mice (McGuire et al, 1992), which was about 30% at one year of age. The latency was not di erent than that observed with normal mice (7/7) treated with MNU (median, 138 days) but the incidence was greater at one year in the LMO1 mice than in normal mice (incidence, 55.6% (15/27 mice).…”

Section: Mnu-induced Lymphomas In Lmo1 and Mgmt+ Transgenic Micementioning

confidence: 99%

“…In mouse strains expressing LMO1, a modest increase in T-cells at all stages of development was noted. Tumor onset correlated with the level of LMO1 expression in individual founder derived substrains, with an incidence of 6 ± 50% and a latency of 5 ± 17 months of age (McGuire et al, 1992;Neale et al, 1995). Most T-cell lymphomas were either CD4+CD8+ or CD47CD8+.…”

Section: Introductionmentioning

confidence: 97%

“…Human T-cell acute lymphocytic leukemia (ALL) provides a model for such processes because chromosomal translocations have been well characterized whereas the contribution of endogenous or environmental mutagens has not. We evaluated a transgenic model of thymic expression of LMO1, a gene located at the t(11;14)(p15;q11) translocation in human T-cell ALL (McGuire et al, 1992). Transgenic expression of LMO1 results in lymphomas in mice.…”

Section: Introductionmentioning

confidence: 99%

“…Transgenic expression of either LMO1 or LMO2 in the mouse thymus results in T-cell lymphomas (McGuire et al, 1992;Neale et al, 1995) presumably through transcriptional activation of genes regulating T-cell development and proliferation. In mouse strains expressing LMO1, a modest increase in T-cells at all stages of development was noted.…”

Section: Introductionmentioning

confidence: 99%

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Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase

et al. 1997

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We evaluated induction of lymphomas by the methylating carcinogen, N-methylnitrosourea [MNU], in transgenic mice expressing both LMO1 and the DNA repair gene, MGMT, in the thymus. The goal was to determine whether environmental mutagens shorten the latency or increase the incidence of LMO1+lymphomas and whether mice transgenic for both LMO1 and MGMT, and thereby able to repair O 6 -methylguanine DNA adducts induced by MNU, would be protected. Mice heterozygous for LMO1 or MGMT were crossed and o spring treated with MNU at 6 weeks of age. MNU induced lymphoma incidence was highest in the LMO1 mice, 91% and lowest in the hMGMT+mice, 15%. MNU induced K-ras mutations in codon 12 in non-MGMT transgenics resulted in a shorter latency of tumors and accounting for half of the early lymphomas in LMO1 mice. The e ect of MNU was abrogated in the LMO1/hMGMT transgenic mice, indicating the ability of MGMT expression to block the carcinogenic e ect of MNU even in cancer prone mice. Thus, methylating agents potentiate lymphomagenesis of LMO1, in part through activation of K-ras and the MAPK pathway, a process which appear to synergize with LMO1 mediated transcription activation. O 6 -alkylguanine DNA-alkyltransferase mediated DNA repair e ectively blocks chemical carcinogenesis in mice carrying the LMO1 oncogene.

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Section: Mnu-induced Lymphomas In Lmo1 and Mgmt+ Transgenic Micesupporting

confidence: 77%

Section: Mnu-induced Lymphomas In Lmo1 and Mgmt+ Transgenic Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase

et al. 1997

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AMLI fusion transcripts in t(3;21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts

Sacchi

Nisson²,

Watkins³

et al. 1994

Genes Chromosomes & Cancer

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The t(3;21)(q26;q22) is associated with chronic myelogenous leukemia in blast crisis (CML-BC), leukemia evolving from (therapy-related) myelodysplasia, and with leukemia following other hematopoietic proliferative diseases. Molecular cytogenetic analysis and cloning of a few t(3;21) cases indicate that the breakpoints are quite heterogeneous even within a specific clinical phenotype. Interestingly some of the (3;21) breakpoints involve the AML1 gene previously found rearranged in the t(8;21) associated with acute myelogenous leukemia. AML1 is related to the Drosophila gene runt and is the human counterpart of the gene for the alpha subunit of the nuclear polyoma enhancer binding protein (PEBP2) also known as the core binding factor (CBF). In the t(3;21) AML1 was found rearranged with EAP, a gene on chromosome 3 encoding a small ribosomal protein, as well as with EV11, another gene on chromosome 3. Here we report our study of six cases of t(3;21). By using fluorescence in situ hybridization (FISH) analysis and AML1 probes we could conclude that at least in two CML-BC cases the breakpoint occurred in the AML1 intron that is disrupted by the t(8;21). An AML1/EAP fusion transcript, different from the one described in a therapy-related myelodysplasia, was detected in both CML-BC cases. This transcript is expected to result in a predicted protein containing the AML1 nuclear binding domain with an attached stretch of 17 amino acids unrelated to the EAP small ribosomal protein. In the other t(3;21) patients we could not detect an AML1/EAP transcript or an AML1/EV11 transcript. This result suggests heterogeneity of the t(3;21) at the molecular level. The AML1 chimeric transcripts identified so far, both in the t(3;21) and in the t(8;21), diverge from the normal transcripts either after exon 5 or exon 6. Here we show that in normal AML1 transcripts different splicing events are seen to occur after AML1 exon 5 as well as exon 6.

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The cysteine-rich LIM domains inhibit DNA binding by the associated homeodomain in Isl-1.

et al. 1993

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Recently, a new class of homeobox genes has been identified, called LIM‐homeobox genes. These genes encode proteins which have two tandemly repeated cysteine motifs, referred to as LIM domains, in addition to a homeodomain. In addition, proteins with only LIM domains have been described but the function of the LIM domain is unknown. We have analysed the function of LIM domains using Isl‐1 as a representative LIM‐homeodomain protein. Employing protein prepared in bacterial cells, we show that the presence of the LIM domain in Isl‐1 inhibits binding of the homeodomain to its DNA target. This in vitro inhibition can be released either by denaturation/renaturation of the protein or by truncation of the LIM domains. A similar inhibition is observed in vivo using reporter constructs. In addition we show that LIM domains in a chimeric protein can inhibit binding of the Ubx homeodomain to its target. The ability of LIM domains to inhibit DNA binding by the homeodomain provides a possible basis for negative regulation of LIM‐homeodomain proteins in vivo.

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Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma.

Abstract: T-cell translocation gene 1 (Ttg-1), also called rhombotin, is deregulated upon translocation into the a/8 T-cell receptor loci in acute lymphoblastic leukemias bearing the t(11;14)(p15;qll). Ttg

Cited by 106 publications

References 61 publications

Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase

Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase

AMLI fusion transcripts in t(3;21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts

The cysteine-rich LIM domains inhibit DNA binding by the associated homeodomain in Isl-1.

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