Distinct gene expression pattern of RUNX1 mutations coordinated by target repression and promoter hypermethylation in acute myeloid leukemia

Abstract

Runt-related transcription factor 1 (RUNX1) is an essential regulator of normal hematopoiesis. Its dysfunction, caused by either fusions or mutations, is frequently reported in acute myeloid leukemia (AML). However, RUNX1 mutations have been largely under-explored compared with RUNX1 fusions mainly due to their elusive genetic characteristics. Here, based on 1741 patients with AML, we report a unique expression pattern associated with RUNX1 mutations in AML. This expression pattern was coordinated by target repression and promoter hypermethylation. We first reanalyzed a joint AML cohort that consisted of three public cohorts and found that RUNX1 mutations were mainly distributed in the Runt domain and almost mutually exclusive with NPM1 mutations. Then, based on RNA-seq data from The Cancer Genome Atlas AML cohort, we developed a 300-gene signature that significantly distinguished the patients with RUNX1 mutations from those with other AML subtypes. Furthermore, we explored the mechanisms underlying this signature from the transcriptional and epigenetic levels. Using chromatin immunoprecipitation sequencing data, we found that RUNX1 target genes tended to be repressed in patients with RUNX1 mutations. Through the integration of DNA methylation array data, we illustrated that hypermethylation on the promoter regions of RUNX1-regulated genes also contributed to dysregulation in RUNX1-mutated AML. This study revealed the distinct gene expression pattern of RUNX1 mutations and the underlying mechanisms in AML development.

Keywords

RUNX1 / gene mutation / acute myeloid leukemia / transcriptional repression / DNA methylation

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (Nos. 81890994, 81770153, 81530003, and 81911530240) and the National Key Research and Development Program of China (No. 2019YFA0905900).

Compliance with ethics guidelines

Jingming Li, Wen Jin, Yun Tan, Beichen Wang, Xiaoling Wang, Ming Zhao, and Kankan Wang declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-020-0815-4 and is accessible for authorized users.

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