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Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

Oncogene volume 26, pages 6937–6947 (2007)Cite this article

Abstract

LYL1, a member of the class II basic helix–loop–helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor 1α promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavy-chain gene rearrangement analyses. Mammalian two-hybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ALL:

acute lymphoblastic leukemia

AML:

acute myeloblastic leukemia

bHLH:

basic helix–loop–helix

CAT:

chloramphenicol acetyltransferase

EF-1α:

human elongation factor 1α

GBD:

Gal4 DNA-binding domain

HDAC:

histone deacetylase

LMO:

LIM-domain-only

MDS:

myelodysplastic syndrome

RT−PCR:

reverse transcription-polymerase chain reaction

TCR:

T-cell receptor

VAD:

VP16-activation domain

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Acknowledgements

We thank Dr Robert E Kingston (Department of Molecular Biology, Massachusetts General Hospital) for providing the HEB cDNA clone. We thank Ms Hiroko Saito and Mr Haruyasu Kohda for their expert technical assistance. We also thank Dr Jun Fan for helpful suggestions. This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology and by a grant from the Inamori Foundation.

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Authors and Affiliations

  1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Y Zhong, L Jiang, S Toyokuni & Y Yamada

  2. Shiga Medical Center for Adults, Moriyama, Shiga, Japan

    H Hiai

  3. Faculty of Nursing and Rehabilitation, Aino University, Ibaraki, Osaka, Japan

    Y Yamada

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  1. Y Zhong
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  2. L Jiang
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Correspondence to Y Yamada.

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Zhong, Y., Jiang, L., Hiai, H. et al. Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice. Oncogene 26, 6937–6947 (2007). https://doi.org/10.1038/sj.onc.1210494

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