Publication Date:
2010-01-23
Description:
The LMO2 oncogene causes a subset of human T cell acute lymphoblastic leukemias (T-ALL), including four cases that arose as adverse events in gene therapy trials. To investigate the cellular origin of LMO2-induced leukemia, we used cell fate mapping to study mice in which the Lmo2 gene was constitutively expressed in the thymus. Lmo2 induced self-renewal of committed T cells in the mice more than 8 months before the development of overt T-ALL. These self-renewing cells retained the capacity for T cell differentiation but expressed several genes typical of hematopoietic stem cells (HSCs), suggesting that Lmo2 might reactivate an HSC-specific transcriptional program. Forced expression of one such gene, Hhex, was sufficient to initiate self-renewal of thymocytes in vivo. Thus, Lmo2 promotes the self-renewal of preleukemic thymocytes, providing a mechanism by which committed T cells can then accumulate additional genetic mutations required for leukemic transformation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McCormack, Matthew P -- Young, Lauren F -- Vasudevan, Sumitha -- de Graaf, Carolyn A -- Codrington, Rosalind -- Rabbitts, Terence H -- Jane, Stephen M -- Curtis, David J -- G0600914/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2010 Feb 12;327(5967):879-83. doi: 10.1126/science.1182378. Epub 2010 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia. mccormack@wehi.edu.au〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20093438" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing
;
Animals
;
Cell Differentiation
;
Cell Transformation, Neoplastic/*genetics
;
DNA-Binding Proteins/*genetics/metabolism
;
Down-Regulation
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Homeodomain Proteins/genetics
;
Humans
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LIM Domain Proteins
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Metalloproteins/*genetics/metabolism
;
Mice
;
Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
;
*Oncogenes
;
Precursor Cells, T-Lymphoid/*physiology/transplantation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics/metabolism/pathology
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Preleukemia/genetics/metabolism/pathology
;
Proto-Oncogene Proteins
;
T-Lymphocyte Subsets
;
T-Lymphocytes/*physiology/transplantation
;
Thymus Gland/metabolism/pathology
;
Transcription Factors/genetics
;
Transcription, Genetic
;
Up-Regulation
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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