TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. / Heyes, Elizabeth; Wilhelmson, Anna S.; Wenzel, Anne; Manhart, Gabriele; Eder, Thomas; Schuster, Mikkel B.; Rzepa, Edwin; Pundhir, Sachin; D’Altri, Teresa; Frank, Anne Katrine; Gentil, Coline; Woessmann, Jakob; Schoof, Erwin M.; Meggendorfer, Manja; Schwaller, Jürg; Haferlach, Torsten; Grebien, Florian; Porse, Bo T.

In: Nature Communications, Vol. 14, 6185, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Heyes, E, Wilhelmson, AS, Wenzel, A, Manhart, G, Eder, T, Schuster, MB, Rzepa, E, Pundhir, S, D’Altri, T, Frank, AK, Gentil, C, Woessmann, J, Schoof, EM, Meggendorfer, M, Schwaller, J, Haferlach, T, Grebien, F & Porse, BT 2023, 'TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression', Nature Communications, vol. 14, 6185. https://doi.org/10.1038/s41467-023-41927-x

APA

Heyes, E., Wilhelmson, A. S., Wenzel, A., Manhart, G., Eder, T., Schuster, M. B., Rzepa, E., Pundhir, S., D’Altri, T., Frank, A. K., Gentil, C., Woessmann, J., Schoof, E. M., Meggendorfer, M., Schwaller, J., Haferlach, T., Grebien, F., & Porse, B. T. (2023). TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. Nature Communications, 14, [6185]. https://doi.org/10.1038/s41467-023-41927-x

Vancouver

Heyes E, Wilhelmson AS, Wenzel A, Manhart G, Eder T, Schuster MB et al. TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. Nature Communications. 2023;14. 6185. https://doi.org/10.1038/s41467-023-41927-x

Author

Heyes, Elizabeth ; Wilhelmson, Anna S. ; Wenzel, Anne ; Manhart, Gabriele ; Eder, Thomas ; Schuster, Mikkel B. ; Rzepa, Edwin ; Pundhir, Sachin ; D’Altri, Teresa ; Frank, Anne Katrine ; Gentil, Coline ; Woessmann, Jakob ; Schoof, Erwin M. ; Meggendorfer, Manja ; Schwaller, Jürg ; Haferlach, Torsten ; Grebien, Florian ; Porse, Bo T. / TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. In: Nature Communications. 2023 ; Vol. 14.

Bibtex

@article{de6503506d334f9a9aed76de29fc2160,
title = "TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression",
abstract = "The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA DM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA NT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA DM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPA DM AML. Elevated CEBPA levels, driven by CEBPA NT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA DM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.",
author = "Elizabeth Heyes and Wilhelmson, {Anna S.} and Anne Wenzel and Gabriele Manhart and Thomas Eder and Schuster, {Mikkel B.} and Edwin Rzepa and Sachin Pundhir and Teresa D{\textquoteright}Altri and Frank, {Anne Katrine} and Coline Gentil and Jakob Woessmann and Schoof, {Erwin M.} and Manja Meggendorfer and J{\"u}rg Schwaller and Torsten Haferlach and Florian Grebien and Porse, {Bo T.}",
note = "Funding Information: Work in the Porse lab was supported by grants from the Copenhagen University Hospital, the Capital Region of Copenhagen, the Independent Research Fund Denmark (9039-00189B) and through a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; Grant Number NNF17CC0027852). This work has been performed in the context of the Danish Research Center for Precision Medicine in Blood Cancers funded by the Danish Cancer Society (R223-A13071) and Greater Copenhagen Health Science Partners. Work in the Grebien lab was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program (European Research Council grant agreement No 636855 and Austrian Science Fund (FWF), grants no. TAI-490 and P35628. Work in the Schoof lab was supported by a grant from the Independent Research Fund Denmark (case no. 2067-00053B). ASW was supported by grants from The Lundbeck Foundation (R303-2018-2868) and The Swedish Research Council (2015-00517). EH was supported by a grant from Forschungsf{\"o}rderung from the Fellinger Krebsforschungsverein. We thank members of the Grebien and Porse laboratories for their discussions. We thank Anna Fossum for her excellent research assistance. Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",
year = "2023",
doi = "10.1038/s41467-023-41927-x",
language = "English",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression

AU - Heyes, Elizabeth

AU - Wilhelmson, Anna S.

AU - Wenzel, Anne

AU - Manhart, Gabriele

AU - Eder, Thomas

AU - Schuster, Mikkel B.

AU - Rzepa, Edwin

AU - Pundhir, Sachin

AU - D’Altri, Teresa

AU - Frank, Anne Katrine

AU - Gentil, Coline

AU - Woessmann, Jakob

AU - Schoof, Erwin M.

AU - Meggendorfer, Manja

AU - Schwaller, Jürg

AU - Haferlach, Torsten

AU - Grebien, Florian

AU - Porse, Bo T.

N1 - Funding Information: Work in the Porse lab was supported by grants from the Copenhagen University Hospital, the Capital Region of Copenhagen, the Independent Research Fund Denmark (9039-00189B) and through a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; Grant Number NNF17CC0027852). This work has been performed in the context of the Danish Research Center for Precision Medicine in Blood Cancers funded by the Danish Cancer Society (R223-A13071) and Greater Copenhagen Health Science Partners. Work in the Grebien lab was supported by the European Union’s Horizon 2020 research and innovation program (European Research Council grant agreement No 636855 and Austrian Science Fund (FWF), grants no. TAI-490 and P35628. Work in the Schoof lab was supported by a grant from the Independent Research Fund Denmark (case no. 2067-00053B). ASW was supported by grants from The Lundbeck Foundation (R303-2018-2868) and The Swedish Research Council (2015-00517). EH was supported by a grant from Forschungsförderung from the Fellinger Krebsforschungsverein. We thank members of the Grebien and Porse laboratories for their discussions. We thank Anna Fossum for her excellent research assistance. Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023

Y1 - 2023

N2 - The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA DM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA NT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA DM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPA DM AML. Elevated CEBPA levels, driven by CEBPA NT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA DM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

AB - The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA DM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA NT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA DM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPA DM AML. Elevated CEBPA levels, driven by CEBPA NT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA DM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

U2 - 10.1038/s41467-023-41927-x

DO - 10.1038/s41467-023-41927-x

M3 - Journal article

C2 - 37794021

AN - SCOPUS:85173748961

VL - 14

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6185

ER -

ID: 371029543