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

Nhu Nguyen; Kristbjorn O Gudmundsson; Anthony R Soltis; Kevin Oakley; Kartik R Roy; Yufen Han; Carmelo Gurnari; Jaroslaw P Maciejewski; Gary Crouch; Patricia Ernst; Clifton L Dalgard; Yang Du

doi:10.1016/j.isci.2021.103679

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

iScience. 2021 Dec 25;25(1):103679. doi: 10.1016/j.isci.2021.103679. eCollection 2022 Jan 21.

Authors

Affiliations

¹ Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
² The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
³ Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
⁵ Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology; Molecular biology.

Grants and funding

R01 CA143193/CA/NCI NIH HHS/United States