Acute promyelocytic leukemia (APL) is characterized by the PML-RARA fusion gene. To identify genetic changes that cooperate with PML-RARA, we performed spectral karyotyping analysis of myeloid leukemias from transgenic PML-RARA mice and from mice coexpressing PML-RARA and BCL2, IL3, activated IL3R, or activated FLT3. A cooperating mutation that enhanced survival (BCL2) was not sufficient to complete transformation and was associated with multiple numeric abnormalities, whereas cooperating mutations that deregulated growth and enhanced survival were associated with normal karyotypes (IL3) or simple karyotypic changes (IL3R, FLT3). Recurring abnormalities included trisomy 15 (49%), trisomy 8 (46%), and -X/-Y (54%). The most common secondary abnormality in human APL is +8 or partial trisomy of 8q24, syntenic to mouse 15. These murine leukemias have a defined spectrum of changes that recapitulates, in part, the cytogenetic abnormalities found in human APL. Our results demonstrate that different cooperating events may generate leukemia via different pathways.