Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Mar 29

PMID 29590629

Citations 109

Authors

Alba Maiques-Diaz

Gary J Spencer

James T Lynch

Filippo Ciceri

Emma L Williams

Fabio M R Amaral

Daniel H Wiseman

William J Harris

Yaoyong Li

Sudhakar Sahoo

James R Hitchin

Daniel P Mould

Emma E Fairweather

Bohdan Waszkowycz

Allan M Jordan

Duncan L Smith

Tim C P Somervaille

Affiliations

Soon will be listed here.

Abstract

Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1's histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.

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