Document Type

Article

Publication Date

5-11-2020

Keywords

JGM, JMG, JAXCC

JAX Source

Genome Biol 2020 May 11; 21(1):110

PMID

32393309

DOI

https://doi.org/10.1186/s13059-020-02030-2

Grant

HG009409,DK107967,RGP0039,Roux Family Endowment,CA034196

Abstract

BACKGROUND: Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RARα in leukemogenesis remain largely unknown.

RESULTS: Using an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RARα induction and perform additional analyses in patient-derived APL cells with native PML-RARα. We discover that PML-RARα mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation.

CONCLUSIONS: Our results not only provide novel topological insights for the roles of PML-RARα in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.

Comments

The authors thank Dr. Oscar Junhong Luo and Dr. Guliang Li for the initial data analysis and Dr. Roel Verhaak for the valuable comments on the manuscript.

This article is licensed under a Creative Commons Attribution 4.0 International License.

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