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

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 incomplete...

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Autores principales: Grebien, Florian, Vedadi, Masoud, Getlik, Matthäus, Giambruno, Roberto, Grover, Amit, Avellino, Roberto, Skucha, Anna, Vittori, Sarah, Kuznetsova, Ekaterina, Smil, David, Barsyte-Lovejoy, Dalia, Li, Fengling, Poda, Gennadiy, Schapira, Matthieu, Wu, Hong, Dong, Aiping, Senisterra, Guillermo, Stukalov, Alexey, Huber, Kilian V. M., Schönegger, Andreas, Marcellus, Richard, Bilban, Martin, Bock, Christoph, Brown, Peter J., Zuber, Johannes, Bennett, Keiryn L., Al-awar, Rima, Delwel, Ruud, Nerlov, Claus, Arrowsmith, Cheryl H., Superti-Furga, Giulio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511833/
https://www.ncbi.nlm.nih.gov/pubmed/26167872
http://dx.doi.org/10.1038/nchembio.1859
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author Grebien, Florian
Vedadi, Masoud
Getlik, Matthäus
Giambruno, Roberto
Grover, Amit
Avellino, Roberto
Skucha, Anna
Vittori, Sarah
Kuznetsova, Ekaterina
Smil, David
Barsyte-Lovejoy, Dalia
Li, Fengling
Poda, Gennadiy
Schapira, Matthieu
Wu, Hong
Dong, Aiping
Senisterra, Guillermo
Stukalov, Alexey
Huber, Kilian V. M.
Schönegger, Andreas
Marcellus, Richard
Bilban, Martin
Bock, Christoph
Brown, Peter J.
Zuber, Johannes
Bennett, Keiryn L.
Al-awar, Rima
Delwel, Ruud
Nerlov, Claus
Arrowsmith, Cheryl H.
Superti-Furga, Giulio
author_facet Grebien, Florian
Vedadi, Masoud
Getlik, Matthäus
Giambruno, Roberto
Grover, Amit
Avellino, Roberto
Skucha, Anna
Vittori, Sarah
Kuznetsova, Ekaterina
Smil, David
Barsyte-Lovejoy, Dalia
Li, Fengling
Poda, Gennadiy
Schapira, Matthieu
Wu, Hong
Dong, Aiping
Senisterra, Guillermo
Stukalov, Alexey
Huber, Kilian V. M.
Schönegger, Andreas
Marcellus, Richard
Bilban, Martin
Bock, Christoph
Brown, Peter J.
Zuber, Johannes
Bennett, Keiryn L.
Al-awar, Rima
Delwel, Ruud
Nerlov, Claus
Arrowsmith, Cheryl H.
Superti-Furga, Giulio
author_sort Grebien, Florian
collection PubMed
description 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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spelling pubmed-45118332016-02-01 Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia Grebien, Florian Vedadi, Masoud Getlik, Matthäus Giambruno, Roberto Grover, Amit Avellino, Roberto Skucha, Anna Vittori, Sarah Kuznetsova, Ekaterina Smil, David Barsyte-Lovejoy, Dalia Li, Fengling Poda, Gennadiy Schapira, Matthieu Wu, Hong Dong, Aiping Senisterra, Guillermo Stukalov, Alexey Huber, Kilian V. M. Schönegger, Andreas Marcellus, Richard Bilban, Martin Bock, Christoph Brown, Peter J. Zuber, Johannes Bennett, Keiryn L. Al-awar, Rima Delwel, Ruud Nerlov, Claus Arrowsmith, Cheryl H. Superti-Furga, Giulio Nat Chem Biol Article 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. 2015-07-13 2015-08 /pmc/articles/PMC4511833/ /pubmed/26167872 http://dx.doi.org/10.1038/nchembio.1859 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Grebien, Florian
Vedadi, Masoud
Getlik, Matthäus
Giambruno, Roberto
Grover, Amit
Avellino, Roberto
Skucha, Anna
Vittori, Sarah
Kuznetsova, Ekaterina
Smil, David
Barsyte-Lovejoy, Dalia
Li, Fengling
Poda, Gennadiy
Schapira, Matthieu
Wu, Hong
Dong, Aiping
Senisterra, Guillermo
Stukalov, Alexey
Huber, Kilian V. M.
Schönegger, Andreas
Marcellus, Richard
Bilban, Martin
Bock, Christoph
Brown, Peter J.
Zuber, Johannes
Bennett, Keiryn L.
Al-awar, Rima
Delwel, Ruud
Nerlov, Claus
Arrowsmith, Cheryl H.
Superti-Furga, Giulio
Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title_full Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title_fullStr Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title_full_unstemmed Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title_short Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
title_sort pharmacological targeting of the wdr5-mll interaction in c/ebpα n-terminal leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511833/
https://www.ncbi.nlm.nih.gov/pubmed/26167872
http://dx.doi.org/10.1038/nchembio.1859
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