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

• Published in: The EMBO journal 2000-09, Vol.19 (17), p.4655-4664
• Main Authors: Lavau, Catherine, Du, Changchun, Thirman, Michael, Zeleznik-Le, Nancy
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Bone marrow; CBP gene; chromatin; chromosomal translocations; chromosome 11; chromosome 16; CREB binding protein; Deoxyribonucleic acid; DNA; DNA Primers; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; E1A protein; Histone-Lysine N-Methyltransferase; Leukemia; Leukemia, Myeloid - pathology; MDS; Mice; MLL; MLL gene; myelodysplasia; myelodysplastic syndrome; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; Myeloid-Lymphoid Leukemia Protein; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proto-Oncogenes; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Translocation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/19.17.4655

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 translocation has been documented almost exclusively in cases of acute leukemia or myelodysplasia secondary to therapy with drugs that target DNA topo isomerase II. The minimal chimeric protein that is produced fuses MLL to the bromodomain, histone acetyltransferase (HAT) domain, EIA‐binding domain and steroid‐receptor coactivator binding domains of CBP. We show that transplantation 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 unusual for other MLL translocations. Structure–function analysis demonstrated that fusion of both the bromodomain and HAT domain of CBP to the amino portion of MLL is required for full in vitro transformation and is sufficient to induce the leukemic phenotype in vivo . This suggests that the leukemic effect of MLL–CBP results from the fusion of the chromatin association and modifying activities of CBP with the DNA binding activities of MLL.