LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways.
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.
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Stephen
S
Smith
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Rati
R
Tripathi
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Charnise
C
Goodings
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Susan
S
Cleveland
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Elizabeth
E
Mathias
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
J Andrew
JA
Hardaway
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Natalina
N
Elliott
Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Yajun
Y
Yi
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Xi
X
Chen
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
James
J
Downing
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Charles
C
Mullighan
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America.
Deborah A
DA
Swing
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America.
Lino
L
Tessarollo
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Liqi
L
Li
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Paul
P
Love
The Methodist Hospital Research Institute, Houston, Texas, United States of America.
Nancy A
NA
Jenkins
The Methodist Hospital Research Institute, Houston, Texas, United States of America.
Neal G
NG
Copeland
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Mary Ann
MA
Thompson
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
Yang
Y
Du
Division of Hematology/Oncology, Vanderbilt University Medical Center and the Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
Utpal P
UP
Davé
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018801:CD2 Antigens / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D024721:E-Box Elements / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009857:Oncogenes; D019683:Penetrance; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D018801:CD2 Antigens; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C078492:HHEX protein, human; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; C490130:Lyl1 protein, mouse