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 2022 Jan 21Abnormal 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.
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. Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation. iScience. 2022 Jan 21;25(1):103679
PMID: 35036869
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