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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.

Original publication

DOI

10.1182/blood-2012-09-458570

Type

Journal article

Journal

Blood

Publication Date

19/09/2013

Volume

122

Pages

2093 - 2103

Keywords

Adaptor Proteins, Signal Transducing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Tumor, Cell Transformation, Neoplastic, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, LIM Domain Proteins, Mice, Mice, Transgenic, Neoplasm Proteins, Neoplastic Stem Cells, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins, T-Lymphocytes, Thymocytes