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

Stephen Smith; Rati Tripathi; Charnise Goodings; Susan Cleveland; Elizabeth Mathias; J Andrew Hardaway; Natalina Elliott; Yajun Yi; Xi Chen; James Downing; Charles Mullighan; Deborah A Swing; Lino Tessarollo; Liqi Li; Paul Love; Nancy A Jenkins; Neal G Copeland; Mary Ann Thompson; Yang Du; Utpal P Davé

doi:10.1371/journal.pone.0085883

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

Journal article

Open access

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

Stephen Smith, Rati Tripathi, Charnise Goodings, Susan Cleveland, Elizabeth Mathias, J Andrew Hardaway, Natalina Elliott, Yajun Yi, Xi Chen, James Downing, …

PloS one, Vol.9(1), pp.e85883-e85883

2014

DOI: https://doi.org/10.1371/journal.pone.0085883

PMCID: PMC3897537

PMID: 24465765

Appears in UM Open Access Research Published in PloS

Abstract

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology

Humans

Molecular Sequence Data

LIM Domain Proteins - metabolism

Neoplasm Proteins - metabolism

Carcinogenesis - metabolism

Promoter Regions, Genetic - genetics

Basic Helix-Loop-Helix Transcription Factors - metabolism

Base Sequence

Leukemia, T-Cell - metabolism

Transcription, Genetic

CD2 Antigens - metabolism

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism

Proto-Oncogene Proteins - metabolism

Mice, Transgenic

Penetrance

Up-Regulation - genetics

Gene Expression Regulation, Leukemic

Transcription Factors - genetics

E-Box Elements - genetics

Homeodomain Proteins - genetics

Carcinogenesis - pathology

Animals

Leukemia, T-Cell - genetics

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics

Cell Line, Tumor

Protein Binding

Mice

Adaptor Proteins, Signal Transducing - metabolism

Leukemia, T-Cell - pathology

Oncogenes

Signal Transduction

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.606 Hematopoietic Stem Cells
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways
Creators: Stephen Smith - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Rati Tripathi - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Charnise Goodings - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Susan Cleveland - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Elizabeth Mathias - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
J Andrew Hardaway - Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
Natalina Elliott - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Yajun Yi - Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
Xi Chen - Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
James Downing - Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America
Charles Mullighan - Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America
Deborah A Swing - Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America
Lino Tessarollo - Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America
Liqi Li - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Paul Love - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Nancy A Jenkins - The Methodist Hospital Research Institute, Houston, Texas, United States of America
Neal G Copeland - The Methodist Hospital Research Institute, Houston, Texas, United States of America
Mary Ann Thompson - Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
Yang Du - Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
Utpal P Davé - Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
Publication Details: PloS one, Vol.9(1), pp.e85883-e85883
Grant note: P30 CA068485 / NCI NIH HHS K08 HL089403 / NHLBI NIH HHS P30 DK058404 / NIDDK NIH HHS T32 CA009592 / NCI NIH HHS DK058404 / NIDDK NIH HHS K08HL089403 / NHLBI NIH HHS P30 CA021765 / NCI NIH HHS R01 CA143193 / NCI NIH HHS I01 BX001799 / BLRD VA R25 GM062459 / NIGMS NIH HHS P30 CA68485 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Public Health Sciences Research
Language: English
Resource Type: Journal article
PMID: 24465765
PMCID: PMC3897537
Record Identifier: 991031598061602976