Acute promyelocytic leukemia (APML) most often is associated with the balanced reciprocal translocation t(15;17) (q22;q11.2) and the expression of both the PML-RAR␣ and RAR␣-PML fusion cDNAs that are formed by this translocation. In this report, we investigated the biological role of a bcr-3 isoform of RAR␣-PML for the development of APML in a transgenic mouse model. Expression of RAR␣-PML alone in the early myeloid cells of transgenic mice did not alter myeloid development or cause APML, but its expression significantly increased the penetrance of APML in mice expressing a bcr-1 isoform of PML-RAR␣ (15% of animals developed APML with PML-RAR␣ alone vs. 57% with both transgenes, P < 0.001). The latency of APML development was not altered substantially by the expression of RAR␣-PML, suggesting that it does not behave as a classical ''second hit'' for development of the disease. Leukemias that arose from doubly transgenic mice were less mature than those from PML-RAR␣ transgenic mice, but they both responded to all-trans retinoic acid in vitro. These findings suggest that PML-RAR␣ drives the development of APML and defines its basic phenotype, whereas RAR␣-PML potentiates this phenotype via mechanisms that are not yet understood.A cute promyelocytic leukemia (APML, or AML M3, based on the French-American-British classification system) comprises about 10% of all new cases of AML. This disease is characterized by the accumulation of promyelocytes in the marrow and the peripheral blood, and a predisposition for bleeding diatheses (reviewed in refs. 1 and 2). The most common genetic abnormality associated with APML is the balanced t(15;17) (q22;q11.2) reciprocal translocation that generates PML-retinoic acid receptor ␣ (RAR␣) and RAR␣-PML fusion cDNAs (1). Although it is common to detect expression of both PML-RAR␣ and RAR␣-PML mRNAs in primary APML cells, the direct link between PML-RAR␣ expression and the development of APML was not demonstrated formally until transgenic expression of PML-RAR␣ in early myeloid cells was shown to cause the development of APML in transgenic mouse models (3-5).The first-generation mouse models demonstrated that expression of PML-RAR␣ in early myeloid cells altered myeloid development in all mice and caused 15-20% of mice to develop a fatal APML-like disease after a latency of 6-18 months (3-5). These findings suggested that PML-RAR␣ directly alters myeloid development and, in doing so, predisposes early myeloid cells to acquire additional mutations (second or subsequent hits) that ultimately cause transformation. The nature of these additional mutations is not yet known, although many patients with APML express the reciprocal RAR␣-PML cDNA, and a significant fraction have loss-of-function mutations in the p53 gene as well (6). The role of the reciprocal fusion for the development of APML has not been addressed previously in transgenic systems, probably because this fusion cDNA is small, containing only a few putative functional domains.Expression analyses of patients with t(15;17) (q22...
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