Researchers recently identified the RUNX3 gene as an oncogene in acute myeloid leukemia (AML) cells in a new study with results reported in the journal Frontiers in Oncology.
RUNX3 belongs to the Runt-related transcription factor (RUNX) family of genes, with other RUNX family genes, RUNX1 and RUNX2, also tied to AML pathogenesis, the researchers explained in their report.
In this study, the researchers performed H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) with AML cells and normal blood cells, including neutrophils, monocytes, and hematopoietic stem cell progenitor cells, to find super-enhancer-associated genes that may be particular to AML. They compared results of ChIP analysis to prognostic data found in The Cancer Genome Atlas for patients with AML. Then, using wild-type and AML mouse models, the researchers performed gene knockdowns to further investigate the results of these analyses through further ChIP-seq and transcriptional approaches.
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RUNX3 was found through ChIP-seq to be a super-enhancer-associated gene with high expression in the AML cells. Additionally, RUNX3 expression appeared to be linked to worse prognosis in patients with AML, according to records found in The Cancer Genome Atlas.
When RUNX3 knockdown was performed on mouse cells with AML, the researchers identified evidence of significantly reduced leukemia progression. With RUNX3 knockdown, AML cells of the peripheral blood reportedly showed a 79.5% reduction on day 28 and 46.9% reduction on day 45, in addition to reduced disease burden found in bone marrow. The spleens and livers of AML mice had been enlarged, but with RUNX3 knockdown there were statistically significant reductions in spleen weight and liver weight.
Inhibition of AML progression with RUNX3 knockdown showed a link to greater DNA damage and apoptosis activity in these cells. ChIP-seq analysis revealed binding of RUNX3 in AML cells to genes associated with repair of DNA damage and genes associated with antiapoptosis pathways.
Quantitative real-time polymerase chain reaction-based analyses showed reductions in the transcription of DNA-repair-associated and antiapoptosis-associated genes in AML cells with RUNX3 knockdown. These included the following DNA-repair-associated genes: Chek1 (36.4% reduction), Ddb1 (48.7%), Rad51c (46.4%), Rpa2 (56.8%), Rpa3 (62.1%), Xrcc1 (56.3%), and Xrcc4 (28.6%). Also included were the following antiapoptosis-related genes: Bcl2 (43.3% reduction), Bcl2l10 (48.5%), Bcl2l12 (63.3%), and Mcl1 (43.4%).
“Altogether, we elucidate that RUNX3 promotes AML progression not only by activating Myc transcription but also by directly regulating oncogene network covering DNA repair and apoptosis,” the researchers concluded in their report. They suggested that RUNX3 may represent a novel target for AML treatment.
Reference
Zhang W, Ma Q, Long B, et al. Runt-related transcription factor 3 promotes acute myeloid leukemia progression. Front Oncol. 2021;11:725336. doi:10.3389/fonc.2021.725336
