TY - JOUR
T1 - C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion
AU - Hayashi, Y.
AU - Hirai, H.
AU - Kamio, N.
AU - Yao, H.
AU - Yoshioka, S.
AU - Miura, Y.
AU - Ashihara, E.
AU - Fujiyama, Y.
AU - Tenen, D. G.
AU - Maekawa, T.
N1 - Funding Information:
We thank Dr Toshio Kitamura (University of Tokyo, Tokyo, Japan) and Dr Keiko Okuda (Kyoto Prefectural University of Medicine, Kyoto, Japan) for providing us with STAT5 mutant vectors and BCR–ABL-expressing vectors, respectively. We are grateful to Mikiko Katakami, Yoko Nakagawa and Yoshiko Manabe for their excellent technical assistance. This work was partly supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and the Global COE Program ‘Center for Frontier Medicine’ from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Takeda Science Foundation, the Kobayashi Foundation for Cancer Research, and Senshin Medical Research Foundation.
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - BCR-ABL
KW - C/EBPb
KW - chronic myeloid leukemia
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U2 - 10.1038/leu.2012.258
DO - 10.1038/leu.2012.258
M3 - Article
C2 - 22948537
AN - SCOPUS:84875232026
SN - 0887-6924
VL - 27
SP - 619
EP - 628
JO - Leukemia
JF - Leukemia
IS - 3
ER -