CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

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CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex. / Schmidt, Luisa; Heyes, Elizabeth; Scheiblecker, Lisa; Eder, Thomas; Volpe, Giacomo; Frampton, Jon; Nerlov, Claus; Valent, Peter; Grembecka, Jolanta; Grebien, Florian.

In: Leukemia, Vol. 33, 24.01.2019, p. 1608-1619.

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Harvard

Schmidt, L, Heyes, E, Scheiblecker, L, Eder, T, Volpe, G, Frampton, J, Nerlov, C, Valent, P, Grembecka, J & Grebien, F 2019, 'CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex', Leukemia, vol. 33, pp. 1608-1619. https://doi.org/10.1038/s41375-019-0382-3

APA

Schmidt, L., Heyes, E., Scheiblecker, L., Eder, T., Volpe, G., Frampton, J., Nerlov, C., Valent, P., Grembecka, J., & Grebien, F. (2019). CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex. Leukemia, 33, 1608-1619. https://doi.org/10.1038/s41375-019-0382-3

Vancouver

Author

Schmidt, Luisa ; Heyes, Elizabeth ; Scheiblecker, Lisa ; Eder, Thomas ; Volpe, Giacomo ; Frampton, Jon ; Nerlov, Claus ; Valent, Peter ; Grembecka, Jolanta ; Grebien, Florian. / CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex. In: Leukemia. 2019 ; Vol. 33. pp. 1608-1619.

Bibtex

@article{6e6eafb7503e407ea04bd0b0ad945b83,
title = "CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex",
abstract = "The gene encoding the transcription factor C/EBPα is mutated in 10–15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.",
author = "Luisa Schmidt and Elizabeth Heyes and Lisa Scheiblecker and Thomas Eder and Giacomo Volpe and Jon Frampton and Claus Nerlov and Peter Valent and Jolanta Grembecka and Florian Grebien",
year = "2019",
month = jan
day = "24",
doi = "10.1038/s41375-019-0382-3",
language = "English",
volume = "33",
pages = "1608--1619",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

AU - Schmidt, Luisa

AU - Heyes, Elizabeth

AU - Scheiblecker, Lisa

AU - Eder, Thomas

AU - Volpe, Giacomo

AU - Frampton, Jon

AU - Nerlov, Claus

AU - Valent, Peter

AU - Grembecka, Jolanta

AU - Grebien, Florian

PY - 2019/1/24

Y1 - 2019/1/24

N2 - The gene encoding the transcription factor C/EBPα is mutated in 10–15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.

AB - The gene encoding the transcription factor C/EBPα is mutated in 10–15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.

UR - http://www.scopus.com/inward/record.url?scp=85060585652&partnerID=8YFLogxK

U2 - 10.1038/s41375-019-0382-3

DO - 10.1038/s41375-019-0382-3

M3 - Article

C2 - 30679799

AN - SCOPUS:85060585652

VL - 33

SP - 1608

EP - 1619

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -