TEL (ETV6)-AML1 (RUNX1) Initiates Self-Renewing Fetal Pro-B Cells in Association with a Transcriptional Program Shared with Embryonic Stem Cells in Mice§

Authors

  • Shinobu Tsuzuki,

    Corresponding author
    1. Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
    • Division of Molecular Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
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    • Telephone: 81-52-762-6111; Fax: 81-52-763-5233

  • Masao Seto

    1. Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
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  • Author contributions: S.T.: conception and design, collection of data, data analysis and interpretation, manuscript writing; M.S.: administrative support, data analysis and interpretation.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 8, 2012.

Abstract

The initial steps involved in the pathogenesis of acute leukemia are poorly understood. The TEL-AML1 fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following the accumulation of secondary genetic “hits.” Here, we show that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML1+ cells nevertheless differentiate terminally in the long term, providing a “window” period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical and sufficient components to establish self-renewing pro-B cells. We further show that TEL-AML1 increases the number of leukemia-initiating cells that are generated in collaboration with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated transcriptional program. STEM CELLS2013;31:236–247

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