Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML
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Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. / Jakobsen, Janus S; Laursen, Linea G; Schuster, Mikkel B; Pundhir, Sachin; Schoof, Erwin; Ge, Ying; d'Altri, Teresa; Vitting-Seerup, Kristoffer; Rapin, Nicolas; Gentil, Coline; Jendholm, Johan; Theilgaard-Mönch, Kim; Reckzeh, Kristian; Bullinger, Lars; Döhner, Konstanze; Hokland, Peter; Fitzgibbon, Jude; Porse, Bo T.
In: Science Advances, Vol. 5, No. 7, eaaw4304, 2019, p. 1-16.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
VL - 5
SP - 1
EP - 16
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 7
M1 - eaaw4304
ER -
ID: 225660019