Expression of a bcr-3 isoform of retinoic acid receptor α-promyelocytic leukemia (RARα-PML) in mice expressing a bcr-1 isoform of PML-RARα is associated with increased penetrance of murine acute promyelocytic leukemia (APL) and the frequent acquisition of an interstitial deletion of one copy of mouse chromosome 2 (del(2)). To determine whether the isoform of RARα-PML is important for these effects, we created mice that expressed a bcr-1 isoform of RARα-PML. Coexpression with the bcr-1 isoform of PML-RARα did not increase the penetrance of APL (7 of 45 animals developed APL with PML-RARα alone vs 12 of 44 with both transgenes; P = .19). Furthermore, the frequency of del(2) in APL cells from doubly transgenic mice was not different from that of mice expressing PML-RARα alone (3 of 6 vs 6 of 12, respectively - P = 1.38 - compared with 11 of 11 for mice coexpressing PML-RARα and bcr-3 RARα-PML). The bcr-1 and bcr-3 isoforms of RARα-PML, therefore, have different biological activities that may be relevant for the pathogenesis of murine APL.