CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia.
CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia.
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DOI：
10.1182/blood-2002-05-1374
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发表时间：
2003-02
期刊：
影响因子：
20.3
通讯作者：
Bao-Tran H. Truong;Young-Jin Lee;T. Lodie;Dorothy J. Park;D. Perrotti;N. Watanabe;H. Koeffler;H. Nakajima;D. Tenen;S. Kogan
中科院分区：
文献类型：
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作者：
Bao-Tran H. Truong;Young-Jin Lee;T. Lodie;Dorothy J. Park;D. Perrotti;N. Watanabe;H. Koeffler;H. Nakajima;D. Tenen;S. Kogan
CCAAT/增强子结合蛋白 (C/EBP) 是调节细胞生长和分化的因子家族。这些因子，特别是 C/EBPα 和 C/EBPepsilon，在正常骨髓细胞生成中具有重要作用。此外，C/EBP 活性的丧失似乎在包括急性髓系白血病 (AML) 在内的骨髓疾病的发病机制中发挥作用。急性早幼粒细胞白血病 (APL) 是 AML 的一种亚型，其中 C/EBP 已被假定发挥作用。在几乎所有 APL 病例中，早幼粒细胞白血病 - 视黄酸受体 α (PML-RARα) 融合蛋白都是由于 t(15;17)(q22;q12) 染色体易位而表达。 PML-RARα 抑制 C/EBPepsilon 的表达，而全反式视黄酸 (tRA)（APL 特别敏感的分化剂）则诱导 C/EBPepsilon 表达。 PML-RARα 也可能抑制 C/EBPα 活性。因此，PML-RARα 对 C/EBP 的影响可能有助于白血病的发展和 APL 对 tRA 的独特敏感性。我们测试了增加 C/EBP 活性会恢复白血病表型的假设。 C/EBPalpha 和 C/EBPepsilon 被引入 FDC-P1 骨髓细胞系和 PML-RARA 转基因小鼠的白血病细胞中。 C/EBP 因子在体外抑制生长并诱导部分分化。在体内，C/EBP 表达的增强可延长生存期。通过使用 C/EBPepsilon 的他莫昔芬反应版本，我们观察到 C/EBPepsilon 可以模仿 tRA 的作用，驱动白血病动物的中性粒细胞分化。我们的结果支持这样的假设：诱导 C/EBP 活性是 tRA 对 APL 的关键作用。此外，我们的研究结果表明，C/EBP 活性的靶向调节可以为 AML 的治疗提供一种新方法。
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/EBPepsilon 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/EBPepsilon 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.