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Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE163470 | GEO | 2021/02/24

REPOSITORIES: GEO

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Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [ChIPseq]

Project description: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.

2021-02-24 | GSE166940 | GEO

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_4cellLines]

2021-02-24 | GSE163469 | GEO

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_MV411]

2021-02-24 | GSE163466 | GEO

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia

Project description:Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia

| PRJNA686276 | ENA

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [ChIPseq]

Project description:Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [ChIPseq]

| PRJNA702445 | ENA

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_MV411]

Project description:Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_MV411]

| PRJNA686277 | ENA

Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_4cellLines]

Project description:Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemia [RNAseq_4cellLines]

| PRJNA686294 | ENA

MYB induces the expression of the oncogenic corepressor SKI in acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) arises through clonal expansion of transformed myeloid progenitor cells. The SKI proto-oncogene is highly upregulated in different solid tumors and leukemic cells, but little is known about its transcriptional regulation during leukemogenesis. MYB is an important hematopoietic transcription factor involved in proliferation as well as differentiation and upregulated in most human acute leukemias. Here, we find that MYB protein binds within the regulatory region of the SKI gene in AML cells. Reporter gene assays using MYB binding sites present in the SKI gene locus show MYB-dependent transcriptional activation. SiRNA-mediated depletion of MYB in leukemic cell lines reveals that MYB is crucial for SKI gene expression. Consistently, we observed a positive correlation of MYB and SKI expression in leukemic cell lines and in samples of AML patients. Moreover, MYB and SKI both were downregulated by treatment with histone deacetylase inhibitors. Strikingly, differentiation of AML cells induced by depletion of MYB is attenuated by overexpression of SKI. Our findings identify SKI as a novel MYB target gene, relevant for the MYB-induced differentiation block in leukemic cells.

| S-EPMC5976475 | biostudies-literature

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.

| S-EPMC5760651 | biostudies-literature

The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia.

Project description:Subtype-specific leukemia oncogenes drive aberrant gene expression profiles that converge on common essential mediators to ensure leukemia self-renewal and inhibition of differentiation. The transcription factor c-MYB functions as one such mediator in a diverse range of leukemias. Here we show for the first time that transcriptional repression of myeloid differentiation associated c-MYB target genes in AML is enforced by the AAA+ ATPase RUVBL2. Silencing RUVBL2 expression resulted in increased binding of c-MYB to these loci and their transcriptional activation. RUVBL2 inhibition resulted in AML cell apoptosis and severely impaired disease progression of established AML in engrafted mice. In contrast, such inhibition had little impact on normal hematopoietic progenitor differentiation. These data demonstrate that RUVBL2 is essential for the oncogenic function of c-MYB in AML by governing inhibition of myeloid differentiation. They also indicate that targeting the control of c-MYB function by RUVBL2 is a promising approach to developing future anti-AML therapies.

| S-EPMC6887538 | biostudies-literature

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