Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

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Abstract

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short 30 kDa C/EBPα translational isoform, termed p30, represents the most common type of CEBPA mutations in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as its down-regulation inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a novel small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30-cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

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Identifying ChIP-seq enrichment using MACS.

Jianxing Feng, Tao Liu, Bo Qin … (2012)

Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ∼3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/.

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Regulation of MLL1 H3K4 methyltransferase activity by its core components.

Yali Dou, Thomas A. Milne, Alexander Ruthenburg … (2006)

Histone H3 Lys4 (H3K4) methylation is a prevalent mark associated with transcription activation. A common feature of several H3K4 methyltransferase complexes is the presence of three structural components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Here we report the first biochemical reconstitution of a functional four-component mixed-lineage leukemia protein-1 (MLL1) core complex. This reconstitution, combined with in vivo assays, allows direct analysis of the contribution of each component to MLL1 enzymatic activity and their roles in transcriptional regulation. Moreover, taking clues from a crystal structure analysis, we demonstrate that WDR5 mediates interactions of the MLL1 catalytic unit both with the common structural platform and with the histone substrate. Mechanistic insights gained from this study can be generalized to the whole family of SET1-like histone methyltransferases in mammals.

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Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.

Yen-Sin Ang, Su-Yi Tsai, Dung-Fang Lee … (2011)

The embryonic stem (ES) cell transcriptional and chromatin-modifying networks are critical for self-renewal maintenance. However, it remains unclear whether these networks functionally interact and, if so, what factors mediate such interactions. Here, we show that WD repeat domain 5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a regulator of ES cell self-renewal. We demonstrate that Wdr5, an "effector" of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. The Oct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators, and furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101231976

Journal ID (pubmed-jr-id): 32624

Journal ID (nlm-ta): Nat Chem Biol

Journal ID (iso-abbrev): Nat. Chem. Biol.

Title: Nature chemical biology

ISSN (Print): 1552-4450

ISSN (Electronic): 1552-4469

Publication date Nihms-submitted: 29 May 2015

Publication date (Electronic): 13 July 2015

Publication date (Print): August 2015

Publication date PMC-release: 01 February 2016

Volume: 11

Issue: 8

Pages: 571-578

Affiliations

[1 ]CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria

[2 ]Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria

[3 ]Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada

[4 ]Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada

[5 ]Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada

[6 ]MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom

[7 ]Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands

[8 ]Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada

[9 ]Department of Laboratory Medicine & Core Facility Genomics, Core Facilities, Medical University Vienna, Vienna 1090, Austria

[10 ]Research Institute of Molecular Pathology (IMP), Vienna 1030, Austria

[11 ]Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada

Author notes

[§ ]correspondence to: Giulio Superti-Furga: gsuperti@ 123456cemm.oeaw.ac.at , phone: +43-1-40160-70001, Cheryl H Arrowsmith: carrow@ 123456uhnresearch.ca , phone: +1-416-946-0881, Florian Grebien: florian.grebien@ 123456lbicr.lbg.ac.at , phone: +43-1-40160-71240

Author Contributions

F.G., M.V., R.G., A.G., R.A., A.Sk., S.V., E.K., D.B.L., F.L, G.S. K.V.M.H. and R.M. planned, performed, and analyzed biochemical, biophysical, cellular or in vivo-experiments. M.G., D.S., G.P., M.S., P.J.B., and R.A. contributed to chemical design and synthesis of OICR-9429 and OICR-0547. H.W, A.D., M.S. solved and analyzed the X-ray crystal structure of WDR5 in complex with OICR-9429. A.St., A.Sc., M.B. and C.B. performed bioinformatic analyses. J.Z., K.L.B., R.D. and C.N. provided access to vital tools and technologies, planned experiments and analyzed results. F.G., M.V., P.J.B., R.A., C.H.A. and G.S.-F. designed the study, planned experiments, analyzed results and wrote the paper.

Article

Manuscript ID: EMS63643

DOI: 10.1038/nchembio.1859

PMC ID: 4511833

PubMed ID: 26167872

SO-VID: 09141f62-7f51-4f46-9df5-46189dd21c29

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Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

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Most cited references 45

Identifying ChIP-seq enrichment using MACS.

Regulation of MLL1 H3K4 methyltransferase activity by its core components.

Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.

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