title: The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal.
abstract: 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.
authors.affiliation: Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia. mccormack@wehi.edu.au
authors.forename: Matthew P
authors.initials: MP
authors.lastname: McCormack
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.forename: Sumitha
authors.initials: S
authors.lastname: Vasudevan
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: de Graaf
authors.forename: Rosalind
authors.initials: R
authors.lastname: Codrington
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
authors.forename: David J
authors.initials: DJ
authors.lastname: Curtis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D054504:Precursor Cells, T-Lymphoid / Q000502:physiology* / Q000637:transplantation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011289:Preleukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors