The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal.
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.
McCormack
Matthew P
MP
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia. mccormack@wehi.edu.au
Young
Lauren F
LF
Vasudevan
Sumitha
S
de Graaf
Carolyn A
CA
Codrington
Rosalind
R
Rabbitts
Terence H
TH
Jane
Stephen M
SM
Curtis
David J
DJ
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
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