C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells

Asumi Yokota; Hideyo Hirai; Ryuichi Sato; Hiroko Adachi; Fumiko Sato; Yoshihiro Hayashi; Atsushi Sato; Naoka Kamio; Yasuo Miura; Masakazu Nakano; Daniel G. Tenen; Shinya Kimura; Kei Tashiro; Taira Maekawa

doi:10.1182/bloodadvances.2018020503

C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells

Asumi Yokota, Hideyo Hirai, Ryuichi Sato, Hiroko Adachi, Fumiko Sato, Yoshihiro Hayashi, Atsushi Sato, Naoka Kamio, Yasuo Miura, Masakazu Nakano, Daniel G. Tenen, Shinya Kimura, Kei Tashiro, Taira Maekawa

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-a (IFN-a) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage² CD34¹ cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.

Original language	English
Pages (from-to)	476-488
Number of pages	13
Journal	Blood Advances
Volume	3
Issue number	3
DOIs	https://doi.org/10.1182/bloodadvances.2018020503
Publication status	Published - 12-02-2019
Externally published	Yes

All Science Journal Classification (ASJC) codes

Hematology

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Yokota, Asumi ; Hirai, Hideyo ; Sato, Ryuichi ; Adachi, Hiroko ; Sato, Fumiko ; Hayashi, Yoshihiro ; Sato, Atsushi ; Kamio, Naoka ; Miura, Yasuo ; Nakano, Masakazu ; Tenen, Daniel G. ; Kimura, Shinya ; Tashiro, Kei ; Maekawa, Taira. / C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells. In: Blood Advances. 2019 ; Vol. 3, No. 3. pp. 476-488.

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title = "C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells",

abstract = "Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-a (IFN-a) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.",

author = "Asumi Yokota and Hideyo Hirai and Ryuichi Sato and Hiroko Adachi and Fumiko Sato and Yoshihiro Hayashi and Atsushi Sato and Naoka Kamio and Yasuo Miura and Masakazu Nakano and Tenen, {Daniel G.} and Shinya Kimura and Kei Tashiro and Taira Maekawa",

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doi = "10.1182/bloodadvances.2018020503",

language = "English",

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C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells. / Yokota, Asumi; Hirai, Hideyo; Sato, Ryuichi; Adachi, Hiroko; Sato, Fumiko; Hayashi, Yoshihiro; Sato, Atsushi; Kamio, Naoka; Miura, Yasuo; Nakano, Masakazu; Tenen, Daniel G.; Kimura, Shinya; Tashiro, Kei; Maekawa, Taira.

In: Blood Advances, Vol. 3, No. 3, 12.02.2019, p. 476-488.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells

AU - Yokota, Asumi

AU - Hirai, Hideyo

AU - Sato, Ryuichi

AU - Adachi, Hiroko

AU - Sato, Fumiko

AU - Hayashi, Yoshihiro

AU - Sato, Atsushi

AU - Kamio, Naoka

AU - Miura, Yasuo

AU - Nakano, Masakazu

AU - Tenen, Daniel G.

AU - Kimura, Shinya

AU - Tashiro, Kei

AU - Maekawa, Taira

PY - 2019/2/12

Y1 - 2019/2/12

N2 - Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-a (IFN-a) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.

AB - Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-a (IFN-a) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.

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JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 3

ER -

C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells

Abstract

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