2. Academic Validation
  3. Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation

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.
Nhu Nguyen 1,  Kristbjorn O Gudmundsson 1,  Anthony R Soltis 2,  Kevin Oakley 1,  Kartik R Roy 1,  Yufen Han 1,  Carmelo Gurnari 3,  Jaroslaw P Maciejewski 3,  Gary Crouch 4,  Patricia Ernst 5 6,  Clifton L Dalgard 2,  Yang Du 1
Affiliations

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.
PMID: 35036869 DOI: 10.1016/j.isci.2021.103679
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.

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