C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion.

• Hayashi, Y

• Hirai, H

• Kamio, N

• Yao, H

• Yoshioka, S

• Miura, Y

• Ashihara, E

• Fujiyama, Y

• Tenen, D G

• Maekawa, T

Abstract

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.

Journal

• Leukemia

  Leukemia 27 (3), 619-628, 2013-03

  Nature Publishing Group

Keywords

• 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

Details

• CRID: 1050845760721646080
• NII Article ID: 20001443660
• NII Article ID: 120005466670
• NII Book ID: AA10668706
• ISSN: 08876924
• ISSN: 14765551
• DOI: 10.1038/leu.2012.258
• HANDLE: 2433/187097
• Web Site: https://www.nature.com/articles/leu2012258.pdf
• Web Site: https://www.nature.com/articles/leu2012258
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN