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

F Grebien; M Vedadi; M Getlik; R Giambruno; A Grover; Roberto Avellino; A Skucha; S Vittori; E Kuznetsova; D Smil; D Barsyte-Lovejoy; FL Li; G Poda; M Schapira; H Wu; AP Dong; G Senisterra; A Stukalov; KVM Huber; A Schonegger; R Marcellus; M Bilban; C Bock; PJ Brown; J Zuber; KL Bennett; R Al-Awar; Ruud Delwel; C Nerlov; CH Arrowsmith; G Superti-Furga

doi:10.1038/NCHEMBIO.1859

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

F Grebien, M Vedadi, M Getlik, R Giambruno, A Grover, Roberto Avellino, A Skucha, S Vittori, E Kuznetsova, D Smil, D Barsyte-Lovejoy, FL Li, G Poda, M Schapira, H Wu, AP Dong, G Senisterra, A Stukalov, KVM Huber, A SchoneggerR Marcellus, M Bilban, C Bock, PJ Brown, J Zuber, KL Bennett, R Al-Awar, Ruud Delwel, C Nerlov, CH Arrowsmith, G Superti-Furga

Hematology

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

218 Citations (Scopus)

Abstract

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-alpha (C/EBP alpha) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBP alpha p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) 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 downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new 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.

Original language	Undefined/Unknown
Pages (from-to)	571-U122
Journal	Nature Chemical Biology
Volume	11
Issue number	8
DOIs	https://doi.org/10.1038/NCHEMBIO.1859
Publication status	Published - 2015

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EMC MM-02-41-03

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Cite this

Grebien, F., Vedadi, M., Getlik, M., Giambruno, R., Grover, A., Avellino, R., Skucha, A., Vittori, S., Kuznetsova, E., Smil, D., Barsyte-Lovejoy, D., Li, FL., Poda, G., Schapira, M., Wu, H., Dong, AP., Senisterra, G., Stukalov, A., Huber, KVM., ... Superti-Furga, G. (2015). Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia. Nature Chemical Biology, 11(8), 571-U122. https://doi.org/10.1038/NCHEMBIO.1859

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title = "Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia",

abstract = "The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-alpha (C/EBP alpha) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBP alpha p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) 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 downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new 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.",

author = "F Grebien and M Vedadi and M Getlik and R Giambruno and A Grover and Roberto Avellino and A Skucha and S Vittori and E Kuznetsova and D Smil and D Barsyte-Lovejoy and FL Li and G Poda and M Schapira and H Wu and AP Dong and G Senisterra and A Stukalov and KVM Huber and A Schonegger and R Marcellus and M Bilban and C Bock and PJ Brown and J Zuber and KL Bennett and R Al-Awar and Ruud Delwel and C Nerlov and CH Arrowsmith and G Superti-Furga",

year = "2015",

doi = "10.1038/NCHEMBIO.1859",

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Grebien, F, Vedadi, M, Getlik, M, Giambruno, R, Grover, A, Avellino, R, Skucha, A, Vittori, S, Kuznetsova, E, Smil, D, Barsyte-Lovejoy, D, Li, FL, Poda, G, Schapira, M, Wu, H, Dong, AP, Senisterra, G, Stukalov, A, Huber, KVM, Schonegger, A, Marcellus, R, Bilban, M, Bock, C, Brown, PJ, Zuber, J, Bennett, KL, Al-Awar, R, Delwel, R, Nerlov, C, Arrowsmith, CH & Superti-Furga, G 2015, 'Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia', Nature Chemical Biology, vol. 11, no. 8, pp. 571-U122. https://doi.org/10.1038/NCHEMBIO.1859

TY - JOUR

T1 - Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia

AU - Grebien, F

AU - Vedadi, M

AU - Getlik, M

AU - Giambruno, R

AU - Grover, A

AU - Avellino, Roberto

AU - Skucha, A

AU - Vittori, S

AU - Kuznetsova, E

AU - Smil, D

AU - Barsyte-Lovejoy, D

AU - Li, FL

AU - Poda, G

AU - Schapira, M

AU - Wu, H

AU - Dong, AP

AU - Senisterra, G

AU - Stukalov, A

AU - Huber, KVM

AU - Schonegger, A

AU - Marcellus, R

AU - Bilban, M

AU - Bock, C

AU - Brown, PJ

AU - Zuber, J

AU - Bennett, KL

AU - Al-Awar, R

AU - Delwel, Ruud

AU - Nerlov, C

AU - Arrowsmith, CH

AU - Superti-Furga, G

PY - 2015

Y1 - 2015

N2 - The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-alpha (C/EBP alpha) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBP alpha p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) 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 downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new 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.

AB - The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-alpha (C/EBP alpha) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBP alpha p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) 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 downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new 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.

U2 - 10.1038/NCHEMBIO.1859

DO - 10.1038/NCHEMBIO.1859

M3 - Article

SN - 1552-4450

VL - 11

SP - 571-U122

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 8

ER -