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Ablation of MYB-dependent leukaemia phenotype in MLL-driven AML correlates with increased expression of MAFB

ABSTRACT: The transcription factor MYB plays a pivotal role in haematopoietic homeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). Our previous work on CEBPA mutants has demonstrated that not all AML types display the same dependency on MYB expression, rather this depends on the nature of the driving mutations. However, whether this difference in MYB expression dependency is a general trend in AML still remains to be further elucidated. In this study, we investigate the importance of MYB in human leukaemia by performing siRNA-mediated knock-down in cell lines modelling AML driven by different genetic lesions. We show that the reduction in proliferation and the concomitant induction of myeloid commitment observed in MLL-driven leukaemia upon suppression of MYB expression is not seen in AML cells with a complex karyotype. By performing transcriptome analysis, we demonstrate that reduction of MYB in the cell line that responds to its manipulation leads to a strong activation of MAFB expression. Correlating with these observations, stratification of publicly available patient data reveals a reciprocal relationship between the expression of MYB and MAFB, highlighting a novel connection between those two factors in such AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149556 | GEO | 2023/04/29

REPOSITORIES: GEO

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Dependence on Myb expression is attenuated in myeloid leukemia with N-terminal CEBPA mutations

Project description:Mutations altering the normal function of C/EBPα are frequent in acute myeloid leukaemia with normal karyotype. MYB, a cooperating partner of C/EBPα, is likewise heavily implicated in AML. Here we investigate how the relative requirement for the transcription factor MYB in AML relates to the particular combinations of wild type and mutated alleles of CEBPA. Through knockdown of Myb in murine cell lines modelling the spectrum of CEBPA mutations we show that the consequences of reduced Myb depend on the mutational status of Cebpa. Importantly, Myb knockdown fails to override the block in myeloid differentiation in cells with biallelic N-terminal C/EBPα mutations, demonstrating for the first time that the dependency on Myb observed in AML is much lower in leukaemia with this combination of mutations. By comparing genome-wide analyses of gene expression following Myb knockdown and ChIP-seq data for the binding of C/EBPα isoforms, we provide evidence for a functional cooperation between C/EBPα and Myb in the maintenance of the leukaemia state. This co-dependency breaks down when both alleles of CEBPA harbour N-terminal mutations, as a subset of C/EBPα-regulated genes only bind the short p30 C/EBPα isoform and, unlike other C/EBPα regulated genes, do so without a requirement for Myb.

2019-03-13 | GSE119348 | GEO

Sharp2019 - AML

Project description:The paper describes a model of acute myeloid leukaemia. Created by COPASI 4.26 (Build 213) This model is described in the article: Optimal control of acute myeloid leukaemia Jesse A. Sharp, Alexander P Browning, Tarunendu Mapder, Kevin Burrage, Matthew J Simpson Journal of Theoretical Biology 470 (2019) 30–42 Abstract: Acute myeloid leukaemia (AML) is a blood cancer affecting haematopoietic stem cells. AML is routinely treated with chemotherapy, and so it is of great interest to develop optimal chemotherapy treatment strategies. In this work, we incorporate an immune response into a stem cell model of AML, since we find that previous models lacking an immune response are inappropriate for deriving optimal control strategies. Using optimal control theory, we produce continuous controls and bang-bang controls, corre- sponding to a range of objectives and parameter choices. Through example calculations, we provide a practical approach to applying optimal control using Pontryagin’s Maximum Principle. In particular, we describe and explore factors that have a profound influence on numerical convergence. We find that the convergence behaviour is sensitive to the method of control updating, the nature of the control, and to the relative weighting of terms in the objective function. All codes we use to implement optimal control are made available. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2019-08-19 | BIOMD0000000798 | BioModels

Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells [RNA-Seq]

Project description:Identification of histone acetylation targets of Kat2a activity in murine models of acute myeloid leukaemia (AML) driven by the MLL-AF9 oncogenic fusion

2020-02-03 | GSE118768 | GEO

Definition of aberrant MYB CBP/P300 complex in AML

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.

2020-12-17 | PXD019708 | Pride

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

Phosphoproteomic profiling of Acute Myeloid Leukaemia

Project description:Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.

2019-12-20 | MSV000084730 | MassIVE

An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

Project description:In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

| EGAS00001004839 | EGA

EVI1-phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal

Project description:The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate effects of posttranslational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). EVI1-WT (wild type), with S436 available for phosphorylation, but not EVI1-S436A, conferred haematopoietic progenitor cell self-renewal associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed affinity reduction to CtBP1, and EVI1-WT showed reduced interaction with CtBP1 compared with EVI1-S463A. The target the motif harbouring S436 is targeted by CDK2 and CDK3 kinases, which both interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared to EVI1-S436A, and a hypo-methylated cell population associated with EVI1-WT expression is not maintained with EVI1-S436A. These data point to a role of the EVI1-S436 phosphorylation for directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may benefit therapy for EVI1-driven leukaemia.

2020-11-01 | GSE157315 | GEO

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 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 derepression. RUVBL2 inhibition induced 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 reveal a central mechanism governing inhibition of myeloid differentiation by c-MYB in AML. They also indicate that targeting the control of c-MYB function by RUVBL2 is likely to be a promising approach to developing future anti-AML therapies.

2020-04-14 | GSE117224 | GEO

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