Dysregulated MAPK signaling pathway in acute myeloid leukemia with RUNX1 mutations

ABSTRACT

Background

Acute myeloid leukemia (AML) is a hematologic malignancy with genetic alterations. RUNX1, which is an essential transcription factor for hematopoiesis, is frequently mutated in AML. Loss-of-function mutation of RUNX1 is correlated with poor prognosis of AML patients. It is urgent to reveal the underlying mechanism.

Research design and methods

TCGA AML, GSE106291, GSE142700, and GSE67609 datasets were used. R package was used to define differentially expressed miRNAs, miRNA target genes, RUNX1-related gene, RUNX directly regulating genes, and so on. The relationship of gene expression with overall survival was analyzed by Cox regression. KEGG and GO analyses were applied to the above-mentioned genesets and overlapped genes. Alteration and importance of MAPK pathway were validated in K562 cells by Western blotting and apoptosis assay in vitro.

Results

RUNX1 regulated MAPK pathway indirectly and directly. MAPK pathway was altered in K562-cell-induced mutated RUNX1, and these cells were more sensitive to AraC after p38 was inhibited.

Conclusions

RUNX1 could modulate MAPK pathway, which may provide a potential therapeutic target for AML patients with RUNX1 mutations.

KEYWORDS:

• AML
• RUNX1
• miRNA
• mRNA
• MAPK

Acknowledgments

The authors thank Yu Liu from Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, for assistance with the bioinformatic analysis.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Xiongwei Cai and Yan Wang drafted the work. Xiongwei Cai and Mingmin He conceived and designed the experiments. Mingmin He and Yongqin Jia analyzed the data. Mingmin He prepared the figures and tables.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81874213) and the National Key Research and Development Program of China (2017YFC1309004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.