Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL
| Autor: | Terence H. Rabbitts, Jacob T. Jackson, Matthew P. McCormack, Nicholas J. Slater, Wei Shi, David J. Curtis, Cedric S. Tremblay, Chayanica Nasa, Benjamin J. Shields |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
LMO2
T-Lymphocytes Cellular differentiation Immunology Mice Transgenic Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Biochemistry Mice Cancer stem cell Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Basic Helix-Loop-Helix Transcription Factors medicine Animals Cluster Analysis Humans T-Cell Acute Lymphocytic Leukemia Protein 1 Adaptor Proteins Signal Transducing Regulation of gene expression Thymocytes Gene Expression Regulation Leukemic Gene Expression Profiling Cell Differentiation Cell Biology Hematology LIM Domain Proteins Gene signature medicine.disease Neoplasm Proteins Haematopoiesis Leukemia Cell Transformation Neoplastic Neoplastic Stem Cells Cancer research TAL1 |
| Zdroj: | Blood. 122:2093-2103 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2012-09-458570 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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