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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Animals
-
Base Sequence
-
Basic Helix-Loop-Helix Transcription Factors / metabolism
-
CD2 Antigens / metabolism
-
Carcinogenesis / metabolism*
-
Carcinogenesis / pathology
-
Cell Line, Tumor
-
E-Box Elements / genetics
-
Gene Expression Regulation, Leukemic
-
Homeodomain Proteins / genetics
-
Humans
-
LIM Domain Proteins / metabolism*
-
Leukemia, T-Cell / genetics
-
Leukemia, T-Cell / metabolism*
-
Leukemia, T-Cell / pathology
-
Mice
-
Mice, Transgenic
-
Molecular Sequence Data
-
Neoplasm Proteins / metabolism
-
Oncogenes
-
Penetrance
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
-
Promoter Regions, Genetic / genetics
-
Protein Binding
-
Proto-Oncogene Proteins / metabolism*
-
Signal Transduction*
-
Transcription Factors / genetics
-
Transcription, Genetic
-
Up-Regulation / genetics
Substances
-
Adaptor Proteins, Signal Transducing
-
Basic Helix-Loop-Helix Transcription Factors
-
CD2 Antigens
-
HHEX protein, human
-
Homeodomain Proteins
-
LIM Domain Proteins
-
LMO2 protein, human
-
Lmo2 protein, mouse
-
Lyl1 protein, mouse
-
Neoplasm Proteins
-
Proto-Oncogene Proteins
-
Transcription Factors