期刊
BLOOD
卷 122, 期 12, 页码 2093-2103出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-09-458570
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资金
- Australian National Health and Medical Research Council (NHMRC) [628386, 1003391]
- Independent Research Institute Infrastructure Support (IRIIS) Scheme from the Australian National Health and Medical Research Council (NHMRC)
- Cancer Council of Victoria
- Leukaemia Foundation of Australia
- Australian Research Council
- Sylvia and Charles Viertel Foundation
- Victorian State Government Operational Infrastructure Grant
- Leukaemia and Lymphoma Research
- Medical Research Council
- Medical Research Council [MR/J000612/1] Funding Source: researchfish
- Wellcome Trust [099246/Z/12/Z] Funding Source: researchfish
- Wellcome Trust [099246/Z/12/Z] Funding Source: Wellcome Trust
- MRC [MR/J000612/1] Funding Source: UKRI
Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.
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