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Acute Myeloid Leukemia
RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1569-1580
Sophie G. Kellaway, Peter Keane, Ella Kennett and Constanze Bonifer
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
ABSTRACT
Hematological malignancies are characterized by a block in differ- entiation, which in many cases is caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein encoded by the t(3;21) translocation linking two transcription factors required for normal hematopoiesis. RUNX1-EVI1 expression is found in myelodysplastic syndrome, second- ary acute myeloid leukemia, and blast crisis of chronic myeloid leukemia; with clinical outcomes being worse than in patients with RUNX1-ETO, RUNX1 or EVI1 mutations alone. RUNX1-EVI1 is usually found as a secondary mutation, therefore the molecular mechanisms underlying how RUNX1-EVI1 alone contributes to poor prognosis are unknown. In order to address this question, we induced expression of RUNX1-EVI1 in hematopoietic cells derived from an embryonic stem cell differentiation model. Induction resulted in disruption of the RUNX1-dependent endothelial-hematopoietic transition, blocked the cell cycle and undermined cell fate decisions in multipotent hematopoi- etic progenitor cells. Integrative analyses of gene expression with chro- matin and transcription factor binding data demonstrated that RUNX1- EVI1 binding caused a re-distribution of endogenous RUNX1 within the genome and interfered with both RUNX1 and EVI1 regulated gene expression programs. In summary, RUNX1-EVI1 expression alone leads to extensive epigenetic reprogramming which is incompatible with healthy blood production.
Introduction
The development of acute myeloid leukemia (AML) is a step-wise process wherein cells acquire multiple additional genetic changes following the occurrence of the initial driver mutation which eventually leads to the development of overt disease. A number of driver mutations, such as the t(8;21) translocation which gives rise to the fusion protein RUNX1-ETO are compatible with a pre-leukemic state.1 However, another fusion protein, RUNX1-EVI1 is found most commonly as a secondary mutation2-4 and is associated with a particularly poor prognosis. The RUNX1-EVI1 onco-fusion protein is a product of the t(3;21)(q26;q22) translocation which links sequences from RUNX1 to the entire length of the MDS-EVI1 or EVI1 (also known as MECOM) locus. Elucidating the molecular basis of the phenotypic changes induced by RUNX1-EVI1 alone is complicated by the fact that it is expressed on a background of other mutations and thus unique transcriptional re- wiring is seen in each patient.5
Both RUNX1 and EVI1 play important roles in normal hematopoiesis and in var- ious hematological malignancies. RUNX1 (also known as AML1) is a transcription factor essential for initial specification of hematopoietic cells,6 and is frequently found to be mutated in leukemia.7,8 RUNX1 contains a DNA-binding domain – the runt homology domain (RUNT) at the N-terminus, which is preserved in RUNX1- EVI1 and a transactivation domain which is lost.7 MDS-EVI1 and EVI1 arise from alternative transcripts from the MECOM gene which have both overlapping and opposing functions – EVI1 can be a repressor of gene transcription, whereas MDS- EVI1 has activating functions.9 MDS-EVI1 is essential for long-term survival of
Correspondence:
CONSTANZE BONIFER
c.bonifer@bham.ac.uk
Received: November 5, 2019. Accepted: April 9, 2020. Pre-published: April 16, 2020.
https://doi.org/10.3324/haematol.2019.241885
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