Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ALLs or lymphoid BC CML. Emergence of the RUNX1mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1translocation to a novel recently described gene partner, PRDM16on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ALL. Two patients presented both RUNX1mutations and RUNX1-PRDM16fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABLwith molecular RUNX1abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ALL.