title: C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion.
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.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Hirai
authors.forename: N
authors.initials: N
authors.lastname: Kamio
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.forename: S
authors.initials: S
authors.lastname: Yoshioka
authors.forename: Y
authors.initials: Y
authors.lastname: Miura
authors.forename: E
authors.initials: E
authors.lastname: Ashihara
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiyama
authors.forename: D G
authors.initials: DG
authors.lastname: Tenen
authors.forename: T
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D018952:Antigens, CD34; D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D016044:Fusion Proteins, bcr-abl