2003年2月
CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia
BLOOD
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- 巻
- 101
- 号
- 3
- 開始ページ
- 1141
- 終了ページ
- 1148
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1182/blood-2002-05-1374
- 出版者・発行元
- AMER SOC HEMATOLOGY
CCAAT/enhancer binding proteins (C/ EBPs) are a family of factors that regulate cell growth and differentiation. These factors, particularly C/EBPalpha and C/EBPepsilon, have important roles in normal myelopoiesis. In addition, loss of C/EBP activity appears to have a role in the pathogenesis of myeloid disorders including acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL) is a subtype of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein is expressed as a result of a t(15;17)(q22; q12) chromosomal translocation. PML-RARalpha. inhibits expression of C/EBPepsilon, whereas all-trans retinoic acid (tRA), a differentiating agent to which APL is particularly susceptible, induces C/EBPepsilon expression. PML-RARalpha may also inhibit C/EBPalpha activity. Thus, the effects of PML-RARalpha on C/EBPs may contribute to both the development of leukemia and the unique sensitivity of APL to tRA. We tested the hypothesis that increasing the activity of C/EBPs would revert the leukemic phenotype. C/EBPalpha and C/EBPe were introduced into the FDC-P1 myeloid cell line and into leukemic cells from PML-RARA transgenic mice. C/EBP factors suppressed growth and induced partial differentiation in vitro. In vivo, enhanced expression of C/EBPs prolonged survival. By using a tamoxifen-responsive version of C/EBPepsilon, we observed that C/EBPe could mimic the effect of tRA, driving neutrophilic differentiation in leukemic animals. Our results support the hypothesis that induction of C/EBP activity is a critical effect of tRA in APL. Furthermore, our findings suggest that targeted modulation of C/EBP activities could provide a new approach to therapy of AML. (C) 2003 by The American Society of Hematology.
- リンク情報
- ID情報
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- DOI : 10.1182/blood-2002-05-1374
- ISSN : 0006-4971
- Web of Science ID : WOS:000180679700049