TY - JOUR
T1 - C/EBPα and C/EBPε induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene
AU - Matsushita, H.
AU - Nakajima, H.
AU - Nakamura, Y.
AU - Tsukamoto, H.
AU - Tanaka, Y.
AU - Jin, G.
AU - Yabe, M.
AU - Asai, S.
AU - Ono, R.
AU - Nosaka, T.
AU - Sugita, K.
AU - Morimoto, A.
AU - Hayashi, Y.
AU - Hotta, T.
AU - Ando, K.
AU - Miyachi, H.
N1 - Funding Information:
We thank Dr Toshio Kitamura (Institute of Medical Science, University of Tokyo, Tokyo, Japan) for providing PLAT-E cells. This study was supported in part by Research and Study Program of Tokai University Educational System General Research Organization and a Grant-in Aid for Scientific Research (C) No. 19591139 from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2008/11/13
Y1 - 2008/11/13
N2 - CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPα and C/EBPε. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPα or C/EBPε was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPα-ER, but not vice versa, thus suggesting that C/EBPε may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPε, as well as C/EBPα, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.
AB - CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPα and C/EBPε. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPα or C/EBPε was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPα-ER, but not vice versa, thus suggesting that C/EBPε may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPε, as well as C/EBPα, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.
KW - Acute myeloid leukemia
KW - CCAAT/enhancer binding protein-α
KW - CCAAT/enhancer binding protein-ε
KW - Mixed lineage leukemia gene
KW - Monocytic differentiation
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U2 - 10.1038/onc.2008.285
DO - 10.1038/onc.2008.285
M3 - Article
C2 - 18776924
AN - SCOPUS:56249118674
SN - 0950-9232
VL - 27
SP - 6749
EP - 6760
JO - Oncogene
JF - Oncogene
IS - 53
ER -
