Cancer Genetics Program, Beth Israel Deaconess Cancer Center; and 2 Department of Medicine and 3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
J Exp Med. 2013 Dec 16;210(13):2793-802. doi: 10.1084/jem.20131121.
Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.
急性早幼粒细胞白血病（APL）是一种血液系统恶性肿瘤，由一种嵌合癌蛋白驱动，该蛋白含有维甲酸受体-α（RARa）的 C 末端与一个 N 末端伙伴融合，最常见的是早幼粒细胞白血病蛋白（PML）。从机制上讲，PML-RARa 作为 RARa 和非 RARa 靶基因的转录抑制剂发挥作用，并拮抗调节众多信号通路的 PML 核体的形成和功能。经验发现，PML-RARa 相关的 APL 对全反式维甲酸（ATRA）和三氧化二砷（ATO）均敏感，并且随后对这些药物作用机制的理解，促使人们努力理解分子事件对 APL 细胞分化、白血病起始细胞（LIC）清除以及体外和体内疾病消除的贡献。至关重要的是，从这些研究中获得的机制见解不仅导致对 APL 本身有了更好的理解，而且还为其他恶性肿瘤提供了宝贵的经验教训。
