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A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA412307PRJNA412430PRJNA412431

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE104309 | GEO | 2018/01/08

SECONDARY ACCESSION(S): PRJNA412307

REPOSITORIES: GEO

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A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia.

Project description:Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

| S-EPMC5764110 | biostudies-literature

A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (RNA-seq)

Project description:Targeting of general coactivators, such as BRD4, is an emerging strategy to interfere with oncogenic transcription factors (TFs) in cancer. However, coactivator perturbations have the potential to influence the function of numerous TFs, thereby resulting in biological pleiotropy. Here we identify TAF12, an 18 kilodalton subunit of TFIID/SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this AML-specific dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of a histone-fold domain fragment of TAF4 can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

2018-01-08 | GSE104308 | GEO

A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (ChIP-seq)

2018-01-08 | GSE104307 | GEO

A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia

Project description:A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia

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A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (ChIP-seq)

Project description:A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (ChIP-seq)

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A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (RNA-seq)

Project description:A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (RNA-seq)

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Peptidomimetic blockade of MYB in acute myeloid leukemia.

Project description:Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.

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Peptidomimetic blockade of MYB in acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy for which treatment options have been largely limited to cytotoxic chemotherapy for the past four decades. Next-generation sequencing and other approaches have identified a spectrum of genomic and epigenomic alterations that contribute to AML initiation and maintenance. The key role of epigenetic modifiers and the reversibility of epigenetic changes have paved the way for evaluation of a new set of drug targets, and facilitated the design of novel candidate treatment strategies. More recently, seven new targeted therapies have been FDA-approved demonstrating successful implementation of the past decades' research. In this review, we will summarize the most recent advances in targeted therapeutics designed for a focused group of key epigenetic regulators in AML, outline their mechanism of action and their current status in clinical development. Furthermore, we will discuss promising new approaches for epigenetic targeted treatment in AML which are currently being tested in pre-clinical trials.

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