Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cluster Analysis
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Humans
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LIM Domain Proteins / genetics*
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LIM Domain Proteins / metabolism
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Mice
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Mice, Transgenic
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Neoplastic Stem Cells / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism
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Thymocytes / metabolism
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Thymocytes / pathology
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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LIM Domain Proteins
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Lmo2 protein, mouse
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Lyl1 protein, mouse
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Neoplasm Proteins
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Proto-Oncogene Proteins
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Tal1 protein, mouse