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Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.

Original publication

DOI

10.1016/j.ccell.2018.01.006

Type

Journal article

Journal

Cancer Cell

Publication Date

12/02/2018

Volume

33

Pages

274 - 291.e8

Keywords

BET inhibition, EZH2, FLT3-ITD, RUNX1, early thymic progenitor leukemia, early thymic progenitors, leukemia propagating cells, leukemic stem cells, Animals, Core Binding Factor Alpha 2 Subunit, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute, Mice, Knockout, Mutation, Myeloid Cells, Signal Transduction, Stem Cells