Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation

iScience

Clifton L. Dalgard¹  Gary Crouch²  Patricia Ernst³  Nhu Nguyen⁴  Kartik R. Roy⁴  Yufen Han⁴  Kristbjorn O. Gudmundsson⁴  Kevin Oakley⁴  Carmelo Gurnari⁵  Jaroslaw P. Maciejewski⁵  Anthony R. Soltis⁶  Yang Du⁶ 

[1] Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA;Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA;Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA;Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA;Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA;The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA;

关键词: Biological sciences;    Molecular biology;    Cell biology;    Cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb 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 Hoxa9/Hoxa10/Myb and a large group of ribosomal protein genes. Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation.

【 授权许可】

Unknown