Abnormal activation of due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying epigenetic mechanisms remain elusive. We found that both SETBP1 and its missense mutant SETBP1(D/N) directly interact with histone methyltransferase MLL1. Using a combination of ChIP-seq and RNA-seq analysis in primary hematopoietic stem and progenitor cells, we uncovered extensive overlap in their genomic occupancy and their cooperation in activating many oncogenic transcription factor genes including and a large group of ribosomal protein genes. Genetic ablation of 1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated -induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in -induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with activation.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749219PMC
http://dx.doi.org/10.1016/j.isci.2021.103679DOI Listing

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