t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming
Institute of Cancer and Genomica Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B152TT, UK
Princess Máxima Centrum for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, The Netherlands
Authors to whom correspondence should be addressed.
Cells 2020, 9(12), 2681; https://doi.org/10.3390/cells9122681
Received: 23 November 2020 / Accepted: 9 December 2020 / Published: 13 December 2020
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness. One of the best-studied AML-subtypes is the t(8;21) AML which carries a translocation fusing sequences encoding the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO gene. The resulting oncoprotein, RUNX1/ETO has been studied for decades, both at the biochemical but also at the systems biology level. It functions as a dominant-negative version of RUNX1 and interferes with multiple cellular processes associated with myeloid differentiation, growth regulation and genome stability. In this review, we summarize our current knowledge of how this protein reprograms normal into malignant cells and how our current knowledge could be harnessed to treat the disease.