Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

Loveena Rishi; Maura Hannon; Mara Salomè; Marie Hasemann; Anne-Katrine Frank; Joana Campos; Jennifer Timoney; Caitriona O'Connor; Mary R Cahill; Bo Porse; Karen Keeshan

doi:10.1182/blood-2013-07-511683

Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

Loveena Rishi, Maura Hannon, Mara Salomè, Marie Hasemann, Anne-Katrine Frank, Joana Campos, Jennifer Timoney, Caitriona O'Connor, Mary R Cahill, Bo Porse, Karen Keeshan

38 Citations (Scopus)

Abstract

The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.

Original language	English
Journal	Blood
Volume	123
Issue number	15
Pages (from-to)	2389-400
Number of pages	12
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2013-07-511683
Publication status	Published - 10 Apr 2014

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title = "Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation",

abstract = "The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.",

author = "Loveena Rishi and Maura Hannon and Mara Salom{\`e} and Marie Hasemann and Anne-Katrine Frank and Joana Campos and Jennifer Timoney and Caitriona O'Connor and Cahill, {Mary R} and Bo Porse and Karen Keeshan",

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T1 - Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

AU - Rishi, Loveena

AU - Hannon, Maura

AU - Salomè, Mara

AU - Hasemann, Marie

AU - Frank, Anne-Katrine

AU - Campos, Joana

AU - Timoney, Jennifer

AU - O'Connor, Caitriona

AU - Cahill, Mary R

AU - Porse, Bo

AU - Keeshan, Karen

PY - 2014/4/10

Y1 - 2014/4/10

N2 - The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.

AB - The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.

U2 - 10.1182/blood-2013-07-511683

DO - 10.1182/blood-2013-07-511683

M3 - Journal article

C2 - 24516045

SN - 0006-4971

VL - 123

SP - 2389

EP - 2400

JO - Blood

JF - Blood

IS - 15

ER -

Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

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