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

MP McCormack, BJ Shields, JT Jackson… - Blood, The Journal …, 2013 - ashpublications.org
MP McCormack, BJ Shields, JT Jackson, C Nasa, W Shi, NJ Slater, CS Tremblay
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
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 …
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.
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