Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL.

Journal article

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.

Authors: McCormack, M; Shields, B; Jackson, J; Nasa, C; Shi, W

• Journal: Blood
• Volume: 122
• Issue: 12
• Pages: 2093-2103
• Publication date: 2013-09-01
• DOI: 10.1182/blood-2012-09-458570
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Cell Line, Tumor; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; Neoplasm Proteins; Cell Differentiation; T-Lymphocytes; Cluster Analysis; Mice, Transgenic; Gene Expression Regulation, Leukemic; Basic Helix-Loop-Helix Transcription Factors; Humans; Neoplastic Stem Cells; Mice; Cell Transformation, Neoplastic; Thymocytes; Animals; Adaptor Proteins, Signal Transducing; LIM Domain Proteins; Gene Expression Profiling