Abstract
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 ofpre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signalingpathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated invivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition invitro and invivo, which reverses aberrant gene expression induced by Ezh2 inactivation.
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