Distal enhancer RNAs regulate alternative promoter usage of MYB and drug resistance in human leukemia cells

MYB is a master transcription factor for the hematopoietic system, and its dysregulation drives the development and therapy resistance of leukemia. However, the mechanisms of MYB regulation and MYB-related therapy resistance are still unclear. Here, we identified two bidirectional enhancer RNAs (eRNAs), MY34UE-AS and MY34UE-S, transcribed from the -34 kb enhancer region of MYB. Both eRNAs promote MYB transcription, proliferation, and migration in human leukemia cells, although through different MYB promoters. MY34UE-AS physically interacts with PURB that binds near MYB TSS2, promoting long-range looping between downstream -34 kb enhancer elements and TSS2, ultimately activating TSS2. While MY34UE-S facilitates DNA looping between upstream -34 kb enhancer elements and TSS1, promoting TSS1 transcription. TSS2, but not TSS1, activity increases in drug resistant leukemia cells, resulting increased expression of N-terminally truncated MYB (ΔN MYB) when total MYB remains unaltered. Compared to full-length MYB, ΔN MYB more potently promotes drug resistance through FTH1 and EZH2 pathway, and targeting MY34UE-AS more efficiently alleviates drug resistance than targeting MY34UE-S. The above relationship of MY34UE-AS/MY34UE-S, TSS2/TSS1, and prognosis was also verified in clinical leukemia samples. For the first time we provide the mechanisms underlying promoter usage of MYB and MYB TSS2 mediated drug resistance in human leukemia.