Ernst Laboratory - Recruitment of MLL1 complex is essential for SETBP1

Journal article

N. Nguyen, K. Gudmundsson, A. Soltis, K. Oakley, K. Roy, Yufen Han, C. Gurnari, J. Maciejewski, G. Crouch, P. Ernst, C. Dalgard, Yang Du
iScience, 2021

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
Nguyen, N., Gudmundsson, K., Soltis, A., Oakley, K., Roy, K., Han, Y., … Du, Y. (2021). Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation. IScience.

Chicago/Turabian Click to copy
Nguyen, N., K. Gudmundsson, A. Soltis, K. Oakley, K. Roy, Yufen Han, C. Gurnari, et al. “Recruitment of MLL1 Complex Is Essential for SETBP1 to Induce Myeloid Transformation.” iScience (2021).

MLA Click to copy
Nguyen, N., et al. “Recruitment of MLL1 Complex Is Essential for SETBP1 to Induce Myeloid Transformation.” IScience, 2021.

BibTeX Click to copy

@article{n2021a,
  title = {Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation},
  year = {2021},
  journal = {iScience},
  author = {Nguyen, N. and Gudmundsson, K. and Soltis, A. and Oakley, K. and Roy, K. and Han, Yufen and Gurnari, C. and Maciejewski, J. and Crouch, G. and Ernst, P. and Dalgard, C. and Du, Yang}
}

Abstract

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.