Recruitment of MLL1 Complex is Essential for SETBP1 to Induce Myeloid Transformation

Overview

Journal iScience

Publisher Cell Press

Date 2022 Jan 17

PMID 35036869

Authors

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

Soon will be listed here.

Abstract

Abnormal activation of due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of 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 and a large group of ribosomal protein genes. Genetic ablation of 1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated -induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in -induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with activation.

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