Ferrara F F, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pelicci P G, Lo Coco F, Nervi C
Department of Histology and Medical Embryology, University of Rome La Sapienza, Italy.
Cancer Res. 2001 Jan 1;61(1):2-7.
Histone deacetylase (HDAC)-dependent transcriptional repression of the retinoic acid (RA)-signaling pathway underlies the differentiation block of acute promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leading to disease remission. We report that transcriptional repression of RA signaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhibitors restored RA-dependent transcriptional activation and triggered terminal differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling. These findings relate alteration of the RA pathway to myeloid leukemogenesis and underscore the potential of transcriptional/differentiation therapy in AML.
组蛋白去乙酰化酶（HDAC）依赖的视黄酸（RA）信号通路转录抑制是急性早幼粒细胞白血病分化阻滞的基础。RA治疗可缓解转录抑制并触发急性早幼粒细胞白血病母细胞的分化，从而导致疾病缓解。我们报告称，RA信号通路的转录抑制是急性髓系白血病（AML）中的一种常见机制。HDAC抑制剂恢复了RA依赖的转录激活，并触发了23例AML患者原代母细胞的终末分化。因此，我们表明，最常见的AML相关融合蛋白AML1/ETO是RA信号通路的HDAC依赖型阻遏物。这些发现将RA通路的改变与髓系白血病发生联系起来，并强调了AML中转录/分化治疗的潜力。
