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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Article number103679
JournaliScience
Volume25
Issue number1
DOIs
StatePublished - 21 Jan 2022
Externally publishedYes

Keywords

  • Biological sciences
  • Cancer
  • Cell biology
  • Molecular biology

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