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PLoS One. 2014 Jan 21;9(1):e85883. doi: 10.1371/journal.pone.0085883. eCollection 2014.

LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways.

Author information

1
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
2
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
3
Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
4
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
5
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
6
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America.
7
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
8
The Methodist Hospital Research Institute, Houston, Texas, United States of America.
9
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
10
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.

Abstract

The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype.

PMID:
24465765
PMCID:
PMC3897537
DOI:
10.1371/journal.pone.0085883
[Indexed for MEDLINE]
Free PMC Article

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