文章基本信息

标题：Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation
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作者：Nhu Nguyen ; Kristbjorn O. Gudmundsson ; Anthony R. Soltis 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：1
页码：1-24
DOI：10.1016/j.isci.2021.103679
语种：English
出版社：Elsevier
摘要：SummaryAbnormal activation ofSETBP1due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation ofHoxa9/Hoxa10/Mybtranscription 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 includingHoxa9/Hoxa10/Myband a large group of ribosomal protein genes. Genetic ablation ofMll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogatedSetbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role inSetbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms withSETBP1activation.Graphical abstractDisplay OmittedHighlights•SETBP1 and mutant SETBP1(D/N) interact directly with multiple regions of MLL1•SETBP1/SETBP1(D/N) co-localizes with MLL1 at oncogenes and ribosomal protein genes•MLL1 is required for SETBP1/SETBP1(D/N)-induced gene activation and AML development•WDR5 inhibition is a promising strategy for treating AMLs withSETBP1activationBiological sciences; Molecular biology; Cell biology; Cancer