TY - JOUR
T1 - Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes
AU - Pattabiraman, Diwakar R.
AU - McGirr, Crystal
AU - Shakhbazov, Konstantin
AU - Barbier, Valerie
AU - Krishnan, Keerthana
AU - Mukhopadhyay, Pamela
AU - Hawthorne, Paula
AU - Trezise, Ann
AU - Ding, Jianmin
AU - Grimmond, Sean M.
AU - Papathanasiou, Peter
AU - Alexander, Warren S.
AU - Perkins, Andrew C.
AU - Levesque, Jean Pierre
AU - Winkler, Ingrid G.
AU - Gonda, Thomas J.
PY - 2014/4/24
Y1 - 2014/4/24
N2 - 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 interactionof c-MybwiththecoactivatorCBP/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 themolecularmechanisms 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 inmyeloid leukemogenesis and suggest disruption of this interaction as a potential therapeutic strategy for acute myeloid leukemia.
AB - 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 interactionof c-MybwiththecoactivatorCBP/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 themolecularmechanisms 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 inmyeloid leukemogenesis and suggest disruption of this interaction as a potential therapeutic strategy for acute myeloid leukemia.
UR - http://www.scopus.com/inward/record.url?scp=84902089745&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-02-413187
DO - 10.1182/blood-2012-02-413187
M3 - Article
SN - 0006-4971
VL - 123
SP - 2682
EP - 2690
JO - Blood
JF - Blood
IS - 17
ER -