The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia
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The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia. / Wellbrock, Jasmin; Behrmann, Lena; Muschhammer, Jana; Modemann, Franziska; Khoury, Kais; Brauneck, Franziska; Bokemeyer, Carsten; Campeau, Eric; Fiedler, Walter.
In: ANN HEMATOL, Vol. 100, No. 12, 12.2021, p. 2933-2941.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia
AU - Wellbrock, Jasmin
AU - Behrmann, Lena
AU - Muschhammer, Jana
AU - Modemann, Franziska
AU - Khoury, Kais
AU - Brauneck, Franziska
AU - Bokemeyer, Carsten
AU - Campeau, Eric
AU - Fiedler, Walter
N1 - © 2021. The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
AB - Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
U2 - 10.1007/s00277-021-04602-z
DO - 10.1007/s00277-021-04602-z
M3 - SCORING: Journal article
C2 - 34333666
VL - 100
SP - 2933
EP - 2941
JO - ANN HEMATOL
JF - ANN HEMATOL
SN - 0939-5555
IS - 12
ER -