Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci P G, Atwater S, Bishop J M
G.W. Hooper Foundation, Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0552, USA.
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2551-6. doi: 10.1073/pnas.94.6.2551.
The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
急性早幼粒细胞白血病（APL）的恶性细胞含有一种相互易位的染色体，该染色体将早幼粒细胞白血病基因（PML）与维甲酸受体α基因（RARα）融合。为了验证嵌合体PMLRARα在白血病发生中起作用的假说，我们在转基因小鼠的髓系细胞中表达了PMLRARα cDNA。PMLRARα转基因小鼠在生命早期表现出中性粒细胞成熟受损，在几个月的时间里以低频率进展为明显的APL。白血病前期状态和白血病都可以移植到非转基因小鼠中，移植的白血病前期可以进展为APL。这种APL重现了人类疾病的特征，包括对维甲酸的反应。维甲酸使白血病细胞在体外和体内分化，引发小鼠白血病前期状态和APL的缓解。我们的结果表明，PMLRARα损害中性粒细胞分化并启动APL的发展。这里描述的转基因小鼠为人类APL提供了一个明显准确的模型，包括肿瘤进展的明确证据。该模型对于探索APL的分子发病机制和维甲酸治疗反应的机制，以及治疗方案的临床前研究应该是有用的。
