Functional interdependence of BRD4 and DOT1L in MLL leukemia

Omer Gilan; Enid Y N Lam; Isabelle Becher; Dave Lugo; Ester Cannizzaro; Gerard Joberty; Aoife Ward; Meike Wiese; Chun Yew Fong; Sarah Ftouni; Dean Tyler; Kym  Stanley; Laura MacPherson; Chen-Fang Weng; Yih-Chih Chan; Margherita Ghisi; David Smil; Christopher Carpenter; Peter Brown; Neil Garton; Marnie E Blewitt; Andrew J Bannister; Tony Kouzarides; Brian J P Huntly; Ricky W Johnstone; Gerard Drewes; Sarah-Jane Dawson; Cheryl H Arrowsmith; Paola Grandi; Rab K Prinjha; Mark A Dawson

doi:10.1038/nsmb.3249

Functional interdependence of BRD4 and DOT1L in MLL leukemia

Omer Gilan, Enid Y N Lam, Isabelle Becher, Dave Lugo, Ester Cannizzaro, Gerard Joberty, Aoife Ward, Meike Wiese, Chun Yew Fong, Sarah Ftouni, Dean Tyler, Kym Stanley, Laura MacPherson, Chen-Fang Weng, Yih-Chih Chan, Margherita Ghisi, David Smil, Christopher Carpenter, Peter Brown, Neil GartonMarnie E Blewitt, Andrew J Bannister, Tony Kouzarides, Brian J P Huntly, Ricky W Johnstone, Gerard Drewes, Sarah-Jane Dawson, Cheryl H Arrowsmith, Paola Grandi, Rab K Prinjha, Mark A Dawson

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

80 Citations (Scopus)

Abstract

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

Original language	English
Pages (from-to)	673-681
Number of pages	9
Journal	Nature Structural & Molecular Biology
Volume	23
Issue number	7
DOIs	https://doi.org/10.1038/nsmb.3249
Publication status	Published - Jul 2016
Externally published	Yes

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Gilan, O., Lam, E. Y. N., Becher, I., Lugo, D., Cannizzaro, E., Joberty, G., Ward, A., Wiese, M., Fong, C. Y., Ftouni, S., Tyler, D., Stanley, K., MacPherson, L., Weng, C.-F., Chan, Y.-C., Ghisi, M., Smil, D., Carpenter, C., Brown, P., ... Dawson, M. A. (2016). Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nature Structural & Molecular Biology, 23(7), 673-681. https://doi.org/10.1038/nsmb.3249

@article{2c3e7c1fa0e64dee8a5fb5a263f4fc22,

title = "Functional interdependence of BRD4 and DOT1L in MLL leukemia",

abstract = "Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.",

author = "Omer Gilan and Lam, {Enid Y N} and Isabelle Becher and Dave Lugo and Ester Cannizzaro and Gerard Joberty and Aoife Ward and Meike Wiese and Fong, {Chun Yew} and Sarah Ftouni and Dean Tyler and Kym Stanley and Laura MacPherson and Chen-Fang Weng and Yih-Chih Chan and Margherita Ghisi and David Smil and Christopher Carpenter and Peter Brown and Neil Garton and Blewitt, {Marnie E} and Bannister, {Andrew J} and Tony Kouzarides and Huntly, {Brian J P} and Johnstone, {Ricky W} and Gerard Drewes and Sarah-Jane Dawson and Arrowsmith, {Cheryl H} and Paola Grandi and Prinjha, {Rab K} and Dawson, {Mark A}",

year = "2016",

month = jul,

doi = "10.1038/nsmb.3249",

language = "English",

volume = "23",

pages = "673--681",

journal = "Nature Structural & Molecular Biology",

issn = "1545-9993",

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Gilan, O, Lam, EYN, Becher, I, Lugo, D, Cannizzaro, E, Joberty, G, Ward, A, Wiese, M, Fong, CY, Ftouni, S, Tyler, D, Stanley, K, MacPherson, L, Weng, C-F, Chan, Y-C, Ghisi, M, Smil, D, Carpenter, C, Brown, P, Garton, N, Blewitt, ME, Bannister, AJ, Kouzarides, T, Huntly, BJP, Johnstone, RW, Drewes, G, Dawson, S-J, Arrowsmith, CH, Grandi, P, Prinjha, RK & Dawson, MA 2016, 'Functional interdependence of BRD4 and DOT1L in MLL leukemia', Nature Structural & Molecular Biology, vol. 23, no. 7, pp. 673-681. https://doi.org/10.1038/nsmb.3249

TY - JOUR

T1 - Functional interdependence of BRD4 and DOT1L in MLL leukemia

AU - Gilan, Omer

AU - Lam, Enid Y N

AU - Becher, Isabelle

AU - Lugo, Dave

AU - Cannizzaro, Ester

AU - Joberty, Gerard

AU - Ward, Aoife

AU - Wiese, Meike

AU - Fong, Chun Yew

AU - Ftouni, Sarah

AU - Tyler, Dean

AU - Stanley, Kym

AU - MacPherson, Laura

AU - Weng, Chen-Fang

AU - Chan, Yih-Chih

AU - Ghisi, Margherita

AU - Smil, David

AU - Carpenter, Christopher

AU - Brown, Peter

AU - Garton, Neil

AU - Blewitt, Marnie E

AU - Bannister, Andrew J

AU - Kouzarides, Tony

AU - Huntly, Brian J P

AU - Johnstone, Ricky W

AU - Drewes, Gerard

AU - Dawson, Sarah-Jane

AU - Arrowsmith, Cheryl H

AU - Grandi, Paola

AU - Prinjha, Rab K

AU - Dawson, Mark A

PY - 2016/7

Y1 - 2016/7

N2 - Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

AB - Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

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U2 - 10.1038/nsmb.3249

DO - 10.1038/nsmb.3249

M3 - Article

AN - SCOPUS:84977604356

SN - 1545-9993

VL - 23

SP - 673

EP - 681

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 7

ER -

Functional interdependence of BRD4 and DOT1L in MLL leukemia

Abstract

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