Rego E M, Wang Z G, Peruzzi D, He L Z, Cordon-Cardo C, Pandolfi P P
Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Exp Med. 2001 Feb 19;193(4):521-29. doi: 10.1084/jem.193.4.521.
The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor alpha (RARalpha) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARalpha oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML(-/-) mice with human cathepsin G (hCG)-PMLRARalpha or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARalpha TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARalpha TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARalpha are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
早幼粒细胞白血病（PML）基因编码一种推测的肿瘤抑制基因，参与细胞凋亡的调控。在绝大多数急性早幼粒细胞白血病（APL）患者中，由于染色体易位，该基因与维甲酸受体α（RARα）基因融合。PML-RARα癌蛋白被认为通过与PML异源二聚化并使其从核体中脱离的能力来拮抗PML的功能。在APL中，正常PML等位基因杂合性的降低可能促进了这一过程。为了确定PML在体内是否作为肿瘤抑制因子发挥作用，以及白血病和上皮癌发病机制中程序性细胞死亡失控的后果是什么，我们将PML（-/-）小鼠与人类组织蛋白酶G（hCG）-PML-RARα或乳腺肿瘤病毒（MMTV）/neu转基因小鼠（TM）进行杂交，这两种小鼠分别是白血病和乳腺癌的模型。PML剂量的逐渐降低导致白血病发病率显著增加，并加速了PML-RARα转基因小鼠白血病的发病。相比之下，PML失活并不影响neu诱导的肿瘤发生。在PML-RARα转基因小鼠的造血细胞中，PML失活导致对分化剂（如视黄酸和维生素D3）的反应受损，以及在促凋亡刺激下具有明显的生存优势。这些结果表明：（a）PML在体内作为肿瘤抑制因子发挥作用，使细胞对促凋亡和分化刺激具有抗性；（b）PML单倍体不足以及PML-RARα对PML的功能损害是APL发病机制中的关键事件；（c）程序性细胞死亡的异常调控在实体瘤和白血病发病机制中发挥不同作用。
