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标题：PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model
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作者：Louise M. Kelly ; Jeffrey L. Kutok ; Ifor R. Williams 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：12
页码：8283-8288
DOI：10.1073/pnas.122233699
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor (RAR). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RAR in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML/RAR from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML/RAR can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML/RAR transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML/RAR transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML/RAR and FLT3-ITD in development of the murine APL phenotype.