Abstract
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.
Highlights
We describe the t(8;21) Acute myeloid leukemia (AML) sub-type and its clinical manifestations, how its structure and biochemistry differs from that of RUNX1 and how it serves as a paradigm for the in-depth analysis of AML subtypes
Acute Myeloid Leukemia (AML) is a heterogeneous disease characterized by proliferation of neoplastic cells with impaired myeloid differentiation
Knock out of the normal RUNX1 allele in Kasumi-1 cells leads to cell cycle arrest [42] and a marked increase in sub-G1 cells and apoptosis [41]. These findings show that complete loss of RUNX1 activity is not tolerable in t(8;21) leukemia and that RUNX1 is required to counterbalance the detrimental effects of
Summary
Chin 1,† , Farnaz Barneh 2,† , Constanze Bonifer 1, *. Princess Máxima Centrum for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, The Netherlands;. Received: 23 November 2020; Accepted: 9 December 2020; Published: 13 December 2020
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