He L Z, Bhaumik M, Tribioli C, Rego E M, Ivins S, Zelent A, Pandolfi P P
Department of Human Genetics and Molecular Biology Program Memorial Sloan-Kettering Cancer Center Sloan-Kettering Institute, New York, NY 10021, USA.
Mol Cell. 2000 Nov;6(5):1131-41. doi: 10.1016/s1097-2765(00)00111-8.
Acute promyelocytic leukemia (APL) is associated with chromosomal translocations that always involve the RARalpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes). Due to the reciprocity of the translocation, X-RARalpha and RARalpha-X fusion proteins coexist in APL blasts. PLZF-RARalpha transgenic mice (TM) develop leukemia that lacks the differentiation block at the promyelocytic stage that characterizes APL. We generated TM expressing RARalpha-PLZF and PLZF-RARalpha in their promyelocytes. RARalpha-PLZF TM do not develop leukemia. However, PLZF-RARalpha/RARalpha-PLZF double TM develop leukemia with classic APL features. We demonstrate that RARalpha-PLZF can interfere with PLZF transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RARalpha mutants and in PLZF-RARalpha/RARalpha-PLZF TM are indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.
急性早幼粒细胞白血病（APL）与染色体易位相关，这些易位总是涉及RARα基因，该基因可与几个不同的位点之一发生可变融合，包括PML或PLZF（X基因）。由于易位的相互性，X-RARα和RARα-X融合蛋白在APL原始细胞中共存。PLZF-RARα转基因小鼠（TM）会发生白血病，其在早幼粒细胞阶段缺乏APL特有的分化阻滞。我们在其早幼粒细胞中生成了表达RARα-PLZF和PLZF-RARα的TM。RARα-PLZF TM不会发生白血病。然而，PLZF-RARα/RARα-PLZF双转基因小鼠会发生具有典型APL特征的白血病。我们证明RARα-PLZF可以干扰PLZF的转录抑制，并且这对APL发病机制至关重要，因为PLZF（-/-）/PLZF-RARα突变体和PLZF-RARα/RARα-PLZF TM中的白血病难以区分。因此，癌症相关易位的两种产物对于确定疾病的独特特征都至关重要。
