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

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

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13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)619-628
Number of pages10
JournalLeukemia
Volume27
Issue number3
DOIs
Publication statusPublished - 01-03-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

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    Hayashi, Y., Hirai, H., Kamio, N., Yao, H., Yoshioka, S., Miura, Y., Ashihara, E., Fujiyama, Y., Tenen, D. G., & Maekawa, T. (2013). C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion. Leukemia, 27(3), 619-628. https://doi.org/10.1038/leu.2012.258