期刊
EMBO JOURNAL
卷 19, 期 17, 页码 4655-4664出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/19.17.4655
关键词
chromosomal translocations; CREB binding protein; leukemia; MDS; MLL
资金
- NCI NIH HHS [CA78431, P01 CA040046, CA40046, R01 CA078431] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P01CA040046, R01CA078431] Funding Source: NIH RePORTER
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 topoisomerase 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 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.
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