Rego E M, Ruggero D, Tribioli C, Cattoretti G, Kogan S, Redner R L, Pandolfi P P
Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan Kettering Institute, New York, NY 10021, USA.
Oncogene. 2006 Mar 23;25(13):1974-9. doi: 10.1038/sj.onc.1209216.
Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.
涉及17号染色体上RARα基因座的复发性染色体易位是急性早幼粒细胞白血病（APL）的标志。RARα基因与可变伙伴（PML、PLZF、NPM、NuMA和STAT5B：X基因）融合，导致表达具有相同RARα部分的APL特异性融合蛋白。为了分析可变的X部分是否会在体内影响融合蛋白的活性，我们在比较的基础上生成并鉴定了NPM/RARα转基因小鼠（TM），其中融合基因在人组织蛋白酶G（hCG）小基因的控制下表达。我们将这些TM中观察到的白血病特征与hCG-PML/RARα和hCG-PLZF/RARα TM中的特征进行了比较。在所有三种转基因模型中，白血病在不同的长时间潜伏期后发生，具有不同的外显率。然而，这三种白血病表现出明显的细胞形态学特征。hCG-NPM/RARα白血病细胞类似于单核母细胞。这种表型与在hCG-PML/RARα TM模型中观察到的情况形成对比，在该模型中白血病阶段的特征是早幼粒细胞的增殖。同样，hCG-PLZF/RARα TM表现出不同的表型，其中终末分化的髓样细胞占主导。重要的是，发现NPM/RARα癌蛋白定位于核仁，这与PML/RARα和PLZF/RARα不同，因此可能干扰NPM的正常功能。与在人类APL患者中观察到的情况类似，我们发现NPM/RARα和PML/RARα白血病，但不是PLZF/RARα白血病，对全反式维甲酸（ATRA）或三氧化二砷（As2O3）治疗有反应。综上所述，我们的结果强调了X部分在决定疾病生物学特性和APL融合癌蛋白活性方面的关键相关性。
