Journal article
Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype
Cancer research (Chicago, Ill.), Vol.66(20), pp.10032-10039
10/15/2006
DOI: 10.1158/0008-5472.CAN-06-2597
PMID: 17047066
Abstract
A critical unanswered question about mixed lineage leukemia (MLL) is how specific MLL fusion partners control leukemia phenotype. The MLL-cyclic AMP-responsive element binding protein-binding protein (CBP) fusion requires both the CBP bromodomain and histone acetyltransferase (HAT) domain for transformation and causes acute myelogenous leukemia (AML), often preceded by a myelodysplastic phase. We did domain-swapping experiments to define whether unique specificities of these CBP domains drive this specific MLL phenotype. Within MLL-CBP, we replaced the CBP bromodomain or HAT domain with P300/CBP-associated factor (P/CAF) or TAF(II)250 bromodomains or the P/CAF or GCN5 HAT domains. HAT, but not bromodomain, substitutions conferred enhanced proliferative capacity in vitro but lacked expression of myeloid cell surface markers normally seen with MLL-CBP. Mice reconstituted with domain-swapped hematopoietic progenitors developed different disease from those with MLL-CBP. This included development of lymphoid disease and lower frequency of the myelodysplastic phase in those mice developing AML. We conclude that both the CBP bromodomain and HAT domain play different but critical roles in determining the phenotype of MLL-CBP leukemia. Our results support an important role for MLL partner genes in determining the leukemia phenotype besides their necessity in leukemogenesis. Here, we find that subtleties in MLL fusion protein domain specificity direct cells toward a specific disease phenotype.
Details
- Title: Subtitle
- Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype
- Creators
- Donna A Santillan - University of Iowa, Obstetrics and GynecologyCatherine M TheislerAmanda S RyanRelja PopovicTara StuartMing-Ming ZhouSerhan AlkanNancy J Zeleznik-Le
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.66(20), pp.10032-10039
- DOI
- 10.1158/0008-5472.CAN-06-2597
- PMID
- 17047066
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- United States
- Grant note
- CA95040 / NCI NIH HHS T32 AI07508 / NIAID NIH HHS CA40046 / NCI NIH HHS
- Language
- English
- Date published
- 10/15/2006
- Academic Unit
- Obstetrics and Gynecology; Internal Medicine
- Record Identifier
- 9983557494502771
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