RUNX1 - Mutations and Acute Myeloid Leukemia

Mutations and Acute Myeloid Leukemia

At least 39 forms of RUNX1 mutation are implicated in various myeloid malignancies. Examples range from RUNX1 point mutations acquired from low-dose radiation leading to myelodysplastic neoplasms (MDN) or therapy-related myeloid neoplasms (t-MN), to chromosomal translocation of the RUNX1 gene with the ETO / MTG8 / RUNX1T1 gene located on chromosome 8q22, t(8; 21), generating a fusion protein AML-ETO, categorized as acute myeloid leukemia (AML) M2.

In t(8; 21), breakpoints frequently occur at intron 5 – 6 of RUNX1 and intron 1b – 2 of ETO, creating chimeric transcripts that inherit the runt domain from RUNX1, and all Nervy homology regions (NHR) 1-4 from ETO. As a consequence, AML-ETO retains the ability to bind at RUNX1 target genes whilst acting as a transcription repressor via the recruitment of corepressors and histone deacetylases, which is an intrinsic function of ETO. Oncogenic potential of AML-ETO is exerted because it blocks differentiation and promote self-renewal in blast cells, resulting in massive accumulation of blasts (>20%) in the bone marrow. This is further characterized histologically by the presence of Auer rods and epigenetically by lysine acetylation on residues 24 and 43. Other actions of AML-ETO that could induce leukemogenesis include downregulation of the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) and increase in the level of intracellular reactive oxygen species, making cells that express AML-ETO more susceptible to additional genetic mutations.