ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression
ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression
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DOI：
10.1182/blood-2005-07-3068
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发表时间：
2006-04-15
期刊：
影响因子：
20.3
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Mueller, BU;Pabst, T;Tenen, DG
转录因子PU.1的严格调控表达对于正常造血至关重要。PU.1基因敲除小鼠发生急性髓性白血病（AML），在一些AML患者群体中观察到PU.1突变。在这里，我们发现，早幼粒细胞白血病-维甲酸受体α（PML-RARA），在急性早幼粒细胞白血病（APL）中发现的t（15;17）易位编码的蛋白质的条件表达，抑制PU. 1的表达，而治疗APL细胞系和原代细胞与全反式维甲酸（ATRA）恢复PU. 1的表达和诱导中性粒细胞分化。ATRA的激活是由PU.1启动子中的一个区域介导的，CEBPB和OCT-1与该区域的结合被诱导。最后，人类APL细胞中PU.1的条件性表达足以触发中性粒细胞分化，而通过小干扰RNA（siRNA）减少PU.1则阻断ATRA诱导的中性粒细胞分化。这是第一份表明PU.1在急性早幼粒细胞白血病中受到抑制，并且ATRA可以恢复携带t（15;17）的细胞中的PU.1表达的报告。
Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-incluced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-incluced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).