Modelling the earliest events of t(8;21) acute myeloid leukaemia in human embryonic stem cell-derived definitive haematopoietic progenitor cells

The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO and occurs in approximately 10% of all acute myeloid leukaemias. RUNX1-ETO transcripts can be detected in utero and in cells of patients in remission, but its sole expression is insufficient to cause overt leukaemia. Given that t(8;21) patient cells present additional mutations, the epigenetic reprogramming directly mediated by RUNX1-ETO remains unclear. To address this question, we generated human Embryonic Stem Cell lines carrying an inducible RUNX1-ETO transgene, which we subsequently differentiated into definitive haematopoietic progenitors. We show that induction of RUNX1-ETO in already formed progenitors (i) blocks differentiation at an immature stage, (ii) induces a cell-type specific and reversible cell cycle arrest, (iii) abrogates the RUNX1-mediated gene expression program by interfering with RUNX1 binding, resulting in downregulation of haematopoietic, cell cycle as well as DNA repair genes, (iv) closes down a large part of the chromatin accessibility pattern present in adult haematopoietic multipotent progenitors and (v) alters the differentiation of a defined sub-population of progenitors. Our data are consistent with the idea that RUNX1-ETO establishes a precondition for leukaemic transformation by maintaining a reservoir of quiescent pre-leukaemic multipotent progenitors with susceptibility to expand upon acquisition of additional oncogenic events