The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal

被引：190

作者：

McCormack, Matthew P. ^{[1
,2
]}

Young, Lauren F. ^{[1
]}

Vasudevan, Sumitha ^{[1
]}

de Graaf, Carolyn A. ^{[3
,4
]}

Codrington, Rosalind ^{[5
]}

Rabbitts, Terence H. ^{[5
]}

Jane, Stephen M. ^{[1
,2
]}

Curtis, David J. ^{[1
,2
]}

机构：

[1] Royal Melbourne Hosp, Rotary Bone Marrow Res Labs, Parkville, Vic 3050, Australia

[2] Univ Melbourne, Dept Med, Parkville, Vic 3010, Australia

[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

[4] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[5] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England

来源：

SCIENCE | 2010年 / 327卷 / 5967期

基金：

英国医学研究理事会;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; T-CELL LEUKEMIA; GENE-THERAPY; CHROMOSOMAL TRANSLOCATIONS; RETROVIRAL INSERTION; PROTEIN RBTN2; SCID-X1; HEMATOPOIESIS; TRANSCRIPTION; ACTIVATION;

D O I：

10.1126/science.1182378

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：879 / 883

页数：5

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