Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia

As a result of the recurring translocation t(11;16) (q23;p13.3), MLL (mixed -lineage leukemia) is fused in frame to CBP (CREB binding protein). This tr anslocation has been documented almost exclusively in cases of acute leukem ia or myelodysplasia secondary to therapy with drugs that target DNA topois omerase II. The minimal chimeric protein that is produced fuses MLL to the bromodomain, histone acetyltransferase (HAT) domain, ELA-binding domain and steroid-receptor coactivator binding domains of CBP, We show that transpla ntation of bone marrow retrovirally transduced with MLL-CBP induces myeloid leukemias in mice that are preceded by a long preleukemic phase similar to the myelodysplastic syndrome (MDS) seen in many t(11;16) patients but unus ual for other MLL translocations. Structure-function analysis demonstrated that fusion of both the bromodomain and HAT domain of CBP to the amino port ion of MLL is required for full in vitro transformation and is sufficient t o induce the leukemic phenotype in vivo. This suggests that the leukemic ef fect of MLL-CBP results from the fusion of the chromatin association and mo difying activities of CBP with the DNA binding activities of MLL.