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

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