Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

Janus S Jakobsen; Linea G Laursen; Mikkel B Schuster; Sachin Pundhir; Erwin Schoof; Ying Ge; Teresa d'Altri; Kristoffer Vitting-Seerup; Nicolas Rapin; Coline Gentil; Johan Jendholm; Kim Theilgaard-Mönch; Kristian Reckzeh; Lars Bullinger; Konstanze Döhner; Peter Hokland; Jude Fitzgibbon; Bo T Porse

doi:10.1126/sciadv.aaw4304

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

Janus S Jakobsen, Linea G Laursen, Mikkel B Schuster, Sachin Pundhir, Erwin Schoof, Ying Ge, Teresa d'Altri, Kristoffer Vitting-Seerup, Nicolas Rapin, Coline Gentil, Johan Jendholm, Kim Theilgaard-Mönch, Kristian Reckzeh, Lars Bullinger, Konstanze Döhner, Peter Hokland, Jude Fitzgibbon, Bo T Porse

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Abstract

The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human CEBPA mutant AML and the corresponding CebpaLp30 mouse model, we identified Nt5e, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.

Original language	English
Article number	eaaw4304
Journal	Science Advances
Volume	5
Issue number	7
Pages (from-to)	1-16
Number of pages	17
ISSN	2375-2548
DOIs	https://doi.org/10.1126/sciadv.aaw4304
Publication status	Published - 2019

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Mutant CEBPA directly drives theexpression ofthetargetable tumor-promoting factor CD73 inA MLFinal published version, 1.49 MBLicence: CC BY-NC

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Jakobsen, J. S., Laursen, L. G., Schuster, M. B., Pundhir, S., Schoof, E., Ge, Y., d'Altri, T., Vitting-Seerup, K., Rapin, N., Gentil, C., Jendholm, J., Theilgaard-Mönch, K., Reckzeh, K., Bullinger, L., Döhner, K., Hokland, P., Fitzgibbon, J., & Porse, B. T. (2019). Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. Science Advances, 5(7), 1-16. [eaaw4304]. https://doi.org/10.1126/sciadv.aaw4304

Jakobsen, JS, Laursen, LG, Schuster, MB , Pundhir, S, Schoof, E, Ge, Y, d'Altri, T, Vitting-Seerup, K, Rapin, N, Gentil, C, Jendholm, J, Theilgaard-Mönch, K , Reckzeh, K, Bullinger, L, Döhner, K, Hokland, P, Fitzgibbon, J & Porse, BT 2019, 'Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML', Science Advances, vol. 5, no. 7, eaaw4304, pp. 1-16. https://doi.org/10.1126/sciadv.aaw4304

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title = "Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML",

abstract = "The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human CEBPA mutant AML and the corresponding CebpaLp30 mouse model, we identified Nt5e, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.",

author = "Jakobsen, {Janus S} and Laursen, {Linea G} and Schuster, {Mikkel B} and Sachin Pundhir and Erwin Schoof and Ying Ge and Teresa d'Altri and Kristoffer Vitting-Seerup and Nicolas Rapin and Coline Gentil and Johan Jendholm and Kim Theilgaard-M{\"o}nch and Kristian Reckzeh and Lars Bullinger and Konstanze D{\"o}hner and Peter Hokland and Jude Fitzgibbon and Porse, {Bo T}",

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doi = "10.1126/sciadv.aaw4304",

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T1 - Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

AU - Jakobsen, Janus S

AU - Laursen, Linea G

AU - Schuster, Mikkel B

AU - Pundhir, Sachin

AU - Schoof, Erwin

AU - Ge, Ying

AU - d'Altri, Teresa

AU - Vitting-Seerup, Kristoffer

AU - Rapin, Nicolas

AU - Gentil, Coline

AU - Jendholm, Johan

AU - Theilgaard-Mönch, Kim

AU - Reckzeh, Kristian

AU - Bullinger, Lars

AU - Döhner, Konstanze

AU - Hokland, Peter

AU - Fitzgibbon, Jude

AU - Porse, Bo T

PY - 2019

Y1 - 2019

N2 - The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human CEBPA mutant AML and the corresponding CebpaLp30 mouse model, we identified Nt5e, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.

AB - The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human CEBPA mutant AML and the corresponding CebpaLp30 mouse model, we identified Nt5e, encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.

U2 - 10.1126/sciadv.aaw4304

DO - 10.1126/sciadv.aaw4304

M3 - Journal article

C2 - 31309149

SN - 2375-2548

VL - 5

SP - 1

EP - 16

JO - Science advances

JF - Science advances

IS - 7

M1 - eaaw4304

ER -

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

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