Pharmacological inhibition of aberrant transcription factor complexes in inversion 16 acute myeloid leukemia

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of 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 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

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Therapeutic remodeling of CBP transcription factor complex controls oncogenic gene expression in acute myeloid leukemia

10.1101/2020.05.05.077156 ◽

2020 ◽

Author(s):

Lauren Forbes ◽

Paolo Cifani ◽

Gerard Minuesa ◽

Celine Chen ◽

Sumiko Takao ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Transcription Factor ◽

Myeloid Leukemia ◽

List Type ◽

Human Cancers ◽

Co Activation ◽

Transcription Factor Complexes ◽

Oncogenic Gene ◽

Acute Myeloid

HighlightsCell-penetrant peptidomimetic inhibitor selectively blocks oncogenic MYB:CBP/P300 activity in diverse leukemias but not normal blood cellsMYB assembles aberrant transcription factor complexes in AML required for programming leukemic gene expressionCBP/P300 sequestration contributes to MYB-dependent leukemogenic gene expression and chromatin organizationSummaryDysregulated 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 MLL, 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. We propose that convergently organized transcription factor complexes in AML cells control oncogenic gene expression programs. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and possibly other human cancers caused by dysregulated gene control.

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The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

Molecular and Cellular Biology ◽

10.1128/mcb.20.6.2075-2086.2000 ◽

2000 ◽

Vol 20 (6) ◽

pp. 2075-2086 ◽

Cited By ~ 98

Author(s):

Ari M. Melnick ◽

Jennifer J. Westendorf ◽

Adam Polinger ◽

Graeme W. Carlile ◽

Sally Arai ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Transcription Factor ◽

Zinc Finger ◽

Transcriptional Repression ◽

Histone Deacetylases ◽

Myeloid Leukemia ◽

Histone Deacetylase Inhibitors ◽

Promyelocytic Leukemia ◽

Promyelocytic Leukemia Zinc Finger ◽

Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

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