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| Status |
Public on Dec 31, 2012 |
| Title |
Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, raising the possibility that MYB may be a therapeutic target. However realization of this potential requires (i) a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis; and (ii) an approach for developing an effective therapeutic. We previously showed that the interaction of Myb with the coactivator CBP/p300 is essential for its transforming activity. Here we use hematopoietic cells from the Booreana mouse strain, which carries a mutation in Myb that prevents interaction with CBP/p300, to examine the requirement for this interaction in myeloid transformation and leukemogenesis. Using this strain and a strain (plt6) carrying a “complementary” mutation in p300, we show that the Myb-p300 interaction is essential for in vitro transformation by the myeloid leukemia oncogenes AML1-ETO, AML1-ETO9a, MLL-ENL, and MLL-AF9. We further show that unlike cells from wild-type (WT) mice, Booreana cells fail to induce leukemia upon transplantation into irradiated recipients following transduction with an AML1-ETO9a retrovirus. These data highlight disruption of the Myb-p300 interaction as a potential therapeutic strategy for AML and suggest that such a strategy would have a useable therapeutic index since Booreana mice, unlike Myb null mice, are viable. Finally we have begun to explore the molecular basis of the these observations by gene expression profiling; this highlighted several genes previously implicated in myeloid leukemogenesis as being differentially expressed between WT and Booreana cells transduced with AML1-ETO9a.
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| Overall design |
Total RNA was obtained from FACS sorted GFP+;c-Kit+ primary bone marrow cells from WT and Booreana mouse strains which had been cultured for 48 hours post-transduction with Control or AML1-ETO9a retroviruses. RNA was extracted from each of 4 samples per group and used to probe Illumina mouse Beadchips array.
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| Contributor(s) |
Shakhbazov K, Patabiraman DR, Gonda TJ |
| Citation(s) |
24596419 |
| |
| Submission date |
Dec 07, 2011 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Konstantin Shakhbazov |
| Organization name |
UQDI
|
| Street address |
Ipswich Road
|
| City |
Brisbane |
| ZIP/Postal code |
4102 |
| Country |
Australia |
| |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA149777 |
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