title: Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes.
abstract: The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, suggesting that MYB may be a therapeutic target in these diseases. However, realization of this potential requires a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis, and an approach for developing an effective therapeutic. We previously showed that the interaction of c-Myb with the coactivator CBP/p300 is essential for its transforming activity. Here, by using cells from Booreana mice which carry a mutant allele of c-Myb, we show that this 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 mice, Booreana cells transduced with AML1-ETO9a or MLL-AF9 retroviruses fail to generate leukemia upon transplantation into irradiated recipients. Finally, we have begun to explore the molecular mechanisms underlying these observations by gene expression profiling. This identified several genes previously implicated in myeloid leukemogenesis and HSC function as being regulated in a c-Myb-p300-dependent manner. These data highlight the importance of the c-Myb-p300 interaction in myeloid leukemogenesis and suggest disruption of this interaction as a potential therapeutic strategy for acute myeloid leukemia.
authors.affiliation: Diamantina Institute.
authors.forename: Diwakar R
authors.initials: DR
authors.lastname: Pattabiraman
authors.forename: Crystal
authors.initials: C
authors.lastname: McGirr
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shakhbazov
authors.forename: Valerie
authors.initials: V
authors.lastname: Barbier
authors.forename: Keerthana
authors.initials: K
authors.lastname: Krishnan
authors.forename: Pamela
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Paula
authors.initials: P
authors.lastname: Hawthorne
authors.forename: Ann
authors.initials: A
authors.lastname: Trezise
authors.forename: Jianmin
authors.initials: J
authors.lastname: Ding
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.forename: Peter
authors.initials: P
authors.lastname: Papathanasiou
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C551356:MLL-AF9 fusion protein, mouse; C493598:MTG8 protein, mouse; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors