AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis.

Koen H.M Prange,Joost H.A Martens,Amit Mandoli,Marko Laakso,Abhishek A Singh

doi:10.18632/oncotarget.14150

Abstract

Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by many genetic variations, including chromosomal translocations
To identify the common binding and gene program of oncofusion proteins associated with acute myeloid leukemia (AML) we used previously identified target regions of PMLRARA in the t(15;17) NB4 cell line [10], AML1-ETO in the t(8;21) Kasumi-1 cell line [6] and CBFB-MYH11 in the inv(16) ME-1 cell line [9] for further analysis (Figure 1A)
This revealed that the two core binding factor-oncofusion proteins, AML1-ETO and CBFBMYH11 differ significantly in their genomic distribution (Figure 1B), with AML1-ETO preferentially targeting distal elements and CBFB-MYH11 mostly promoter bound

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by many genetic variations, including chromosomal translocations. AML is a progressive malignant disease and leads to deranged populations of red blood cells, platelets, and normal white blood cells in bone marrow. AML is the most common form of acute leukemia in adults, is more prevalent in ageing populations and is responsible for ~1% of cancer deaths worldwide [1, 2]. AML is a potentially curable disease, only a minority of patients are cured with current therapies. A large fraction of AMLs is associated with non-random chromosomal translocations [2, 3] that often result in gene rearrangement and expression of an oncofusion protein. Gene rearrangements are believed to provide crucial ground work for cell transformation and initiation of leukemia. Studies have shown that targeting or silencing of these fusion transcripts in-vitro leads to reversal of leukemogenesis, decreased proliferation and differentiation [4]

Methods

Results

Conclusion