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

iScience (Jan 2022)

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

Affiliations

Nhu Nguyen: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Kristbjorn O. Gudmundsson: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Anthony R. Soltis: The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Kevin Oakley: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Kartik R. Roy: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Yufen Han: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Carmelo Gurnari: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Jaroslaw P. Maciejewski: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Gary Crouch: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Patricia Ernst: Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA
Clifton L. Dalgard: The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Yang Du: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; Corresponding author

Journal volume & issue: Vol. 25, no. 1
p. 103679

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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