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Definition of aberrant MYB CBP/P300 complex in AML

ABSTRACT: Dysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. Thus, aberrantly organized transcription factor complexes control convergent gene expression programs in AML cells. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and other human cancers caused by dysregulated gene control.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Acute Myeloid Leukemia Cell Line

DISEASE(S): Acute Leukemia

SUBMITTER: Alex Kentsis

LAB HEAD: Alex Kentsis

PROVIDER: PXD019708 | Pride | 2020-12-17

REPOSITORIES: Pride

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			Action	DRS
	MS195372LUM_alex_Kentsis_LF1.raw	Raw
	MS195372LUM_alex_Kentsis_LF10.raw	Raw
	MS195372LUM_alex_Kentsis_LF11.raw	Raw
	MS195372LUM_alex_Kentsis_LF12.raw	Raw
	MS195372LUM_alex_Kentsis_LF13.raw	Raw

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Project description: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. 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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Definition of aberrant MYB CBP/P300 complex in AML

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