Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia

Bianca Y Pingul; Hua Huang; Qingzhou Chen; Fatemeh Alikarami; Zhen Zhang; Jun Qi; Kathrin M Bernt; Shelley L Berger; Zhendong Cao; Junwei Shi

doi:10.1016/j.isci.2022.105139

Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia

iScience. 2022 Sep 15;25(10):105139. doi: 10.1016/j.isci.2022.105139. eCollection 2022 Oct 21.

Authors

Bianca Y Pingul^{1

2

3

4}, Hua Huang^{3

5}, Qingzhou Chen^{3

4}, Fatemeh Alikarami⁶, Zhen Zhang^{3

5}, Jun Qi⁷, Kathrin M Bernt^{6

8}, Shelley L Berger^{3

5}, Zhendong Cao^{1

3

4}, Junwei Shi^{1

3

4}

Affiliations

¹ Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
⁸ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA 19104, USA.

Abstract

Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed transcription factor (TF) vulnerabilities in leukemia and uncovered TF clusters that exhibit context-specific vulnerabilities within and between different subtypes of leukemia. Among these TF clusters, we demonstrated that acute myeloid leukemia (AML) with high IRF8 expression was addicted to MEF2D. MEF2D and IRF8 form an autoregulatory loop via direct binding to mutual enhancer elements. One important function of this circuit in AML is to sustain PU.1/MEIS1 co-regulated transcriptional outputs via stabilizing PU.1's chromatin occupancy. We illustrated that AML could acquire dependency on this circuit through various oncogenic mechanisms that results in the activation of their enhancers. In addition to forming a circuit, MEF2D and IRF8 can also separately regulate gene expression, and dual perturbation of these two TFs leads to a more robust inhibition of AML proliferation. Collectively, our results revealed a TF circuit essential for AML survival.

Keywords: Biological sciences; Cancer; Transcriptomics.

Abstract

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