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C/EBP? 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 ? (C/EBP?), a regulator for 'emergency granulopoiesis,' in the pathogenesis of CP-CML was examined. C/EBP? 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/EBP?, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBP?-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBP? 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/EBP?-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBP? is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBP?-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.

SUBMITTER: Hayashi Y 

PROVIDER: S-EPMC4506742 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Hayashi Y Y   Hirai H H   Kamio N N   Yao H H   Yoshioka S S   Miura Y Y   Ashihara E E   Fujiyama Y Y   Tenen D G DG   Maekawa T T  

Leukemia 20120905 3

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 H  ...[more]