C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion.
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説明
The BCR-ABL fusion oncoprotein accelerates differentiation and proliferation of myeloid cells during the chronic phase of chronic myeloid leukemia (CP-CML). Here, the role of CCAAT/enhancer binding protein β (C/EBPβ), a regulator for 'emergency granulopoiesis, ' in the pathogenesis of CP-CML was examined. C/EBPβ expression was upregulated in Lineage(-) CD34(+) CD38(-) hematopoietic stem cells (HSCs) and myeloid progenitors isolated from bone marrow of patients with CP-CML. In EML cells, a mouse HSC line, BCR-ABL upregulated C/EBPβ, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBPβ-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBPβ knockout bone marrow cells survived longer than mice that received BCR-ABL-transduced wild-type (WT) bone marrow cells. Significantly higher levels of leukemic stem cells were maintained in BCR-ABL-transduced C/EBPβ-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBPβ is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBPβ-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.
収録刊行物
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- Leukemia
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Leukemia 27 (3), 619-628, 2013-03
Nature Publishing Group
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キーワード
- C/EBPβ
- BCR–ABL
- chronic myeloid leukemia
- Animals
- Antigens, CD34/metabolism
- Blotting, Western
- Bone Marrow/metabolism
- Bone Marrow/pathology
- Bone Marrow Transplantation
- CCAAT-Enhancer-Binding Protein-beta/physiology
- Cell Differentiation
- Cell Proliferation
- Female
- Flow Cytometry
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myeloid Cells/metabolism
- Myeloid Cells/pathology
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- STAT5 Transcription Factor
- Stem Cells/metabolism
- Stem Cells/pathology
詳細情報 詳細情報について
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- CRID
- 1050845760721646080
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- NII論文ID
- 20001443660
- 120005466670
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- NII書誌ID
- AA10668706
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- ISSN
- 08876924
- 14765551
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- HANDLE
- 2433/187097
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- PubMed
- 22948537
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- IRDB
- Crossref
- CiNii Articles
- KAKEN
- OpenAIRE
