Characterizing alternative splicing landscape by RUNX1/ETO reveals novel vulnerabilities in t(8;21) leukemia

t(8;21) is one of the most frequent types of pediatric leukemia driven by fusion transcription factor RUNX1/ETO (RE) and secondary mutations. RE affects gene expression by recruiting epigenetic repressors to its binding sites blocks differentiation while enhances self-renewal of hematopoietic stem cells. Beside gene-level effects, we were interested to know whether RE also regulates alternative splicing as another complexity layer. We generated an in silico pipeline of different bioinformatics sources to identify alternatively spliced genes in a corresponding cell line and patient samples with knockdown of RE. We identified 378 alternatively spliced genes, 75% of which were predicted to be potentially protein coding, while the rest were non-coding RNAs. We found 2 mechanisms for regulating alternative splicing by RE:1)regulation of non-canonical transcription start sites,2) affecting the expression level or function of 42 RNA binding proteins and splicing factors. These novel transcripts, beside having functional roles, may serve as reservoir of immunogenic peptides for immunotherapy of t(8;21).

Publication History

Article published online:
17 May 2022