Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia

Alba Maiques-Diaz; Gary Spencer; James Lynch; Filippo Ciceri; Emma Williams; Fabio Amaral; Daniel Wiseman; Yaoyong Li; Sudhakar Sahoo; James Hitchin; Daniel Mould; Emma Fairweather; Bohdan Waszkowycz; Allan Jordan; Duncan Smith; Timothy Somervaille

doi:10.1016/j.celrep.2018.03.012

Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia

Alba Maiques-Diaz, Gary Spencer, James Lynch, Filippo Ciceri, Emma Williams, Fabio Amaral, Daniel Wiseman, Yaoyong Li, Sudhakar Sahoo, James Hitchin, Daniel Mould, Emma Fairweather, Bohdan Waszkowycz, Allan Jordan, Duncan Smith, Timothy Somervaille

Research output: Contribution to journal › Article › peer-review

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 which 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 up regulation of nearby, subordinate genes.

Original language	English
Pages (from-to)	3641-3659
Number of pages	19
Journal	Cell Reports
Volume	22
Issue number	13
Early online date	27 Mar 2018
DOIs	https://doi.org/10.1016/j.celrep.2018.03.012
Publication status	Published - 27 Mar 2018

Keywords

GFI1
LSD1
MLL
acetylation
acute myeloid leukemia
methylation

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.03.012Licence: CC BY

Cite this

Maiques-Diaz, A., Spencer, G., Lynch, J., Ciceri, F., Williams, E., Amaral, F., Wiseman, D., Li, Y., Sahoo, S., Hitchin, J., Mould, D., Fairweather, E., Waszkowycz, B., Jordan, A., Smith, D., & Somervaille, T. (2018). Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Reports, 22(13), 3641-3659. https://doi.org/10.1016/j.celrep.2018.03.012

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title = "Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia",

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{\textquoteright}s histone demethylase activity. However, we observed that rapid, extensive drug-induced changes intranscription 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 ofLSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1 which is bound to a discrete set of enhancers located close to transcription factor genes which 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 up regulation of nearby, subordinate genes.",

keywords = "GFI1, LSD1, MLL, acetylation, acute myeloid leukemia, methylation",

author = "Alba Maiques-Diaz and Gary Spencer and James Lynch and Filippo Ciceri and Emma Williams and Fabio Amaral and Daniel Wiseman and Yaoyong Li and Sudhakar Sahoo and James Hitchin and Daniel Mould and Emma Fairweather and Bohdan Waszkowycz and Allan Jordan and Duncan Smith and Timothy Somervaille",

year = "2018",

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day = "27",

doi = "10.1016/j.celrep.2018.03.012",

language = "English",

volume = "22",

pages = "3641--3659",

journal = "Cell Reports",

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Maiques-Diaz, A, Spencer, G, Lynch, J, Ciceri, F, Williams, E, Amaral, F, Wiseman, D , Li, Y, Sahoo, S, Hitchin, J, Mould, D, Fairweather, E, Waszkowycz, B, Jordan, A, Smith, D & Somervaille, T 2018, 'Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia', Cell Reports, vol. 22, no. 13, pp. 3641-3659. https://doi.org/10.1016/j.celrep.2018.03.012

TY - JOUR

T1 - Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia

AU - Maiques-Diaz, Alba

AU - Spencer, Gary

AU - Lynch, James

AU - Ciceri, Filippo

AU - Williams, Emma

AU - Amaral, Fabio

AU - Wiseman, Daniel

AU - Li, Yaoyong

AU - Sahoo, Sudhakar

AU - Hitchin, James

AU - Mould, Daniel

AU - Fairweather, Emma

AU - Waszkowycz, Bohdan

AU - Jordan, Allan

AU - Smith, Duncan

AU - Somervaille, Timothy

PY - 2018/3/27

Y1 - 2018/3/27

N2 - 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 intranscription 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 ofLSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1 which is bound to a discrete set of enhancers located close to transcription factor genes which 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 up regulation of nearby, subordinate genes.

AB - 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 intranscription 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 ofLSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1 which is bound to a discrete set of enhancers located close to transcription factor genes which 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 up regulation of nearby, subordinate genes.

KW - GFI1

KW - LSD1

KW - MLL

KW - acetylation

KW - acute myeloid leukemia

KW - methylation

U2 - 10.1016/j.celrep.2018.03.012

DO - 10.1016/j.celrep.2018.03.012

M3 - Article

C2 - 29590629

VL - 22

SP - 3641

EP - 3659

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -

Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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