Dataset Information

Genome-wide binding of transcription factors in inv(16) acute myeloid leukemia.

ABSTRACT: The inv(16) translocation is associated with 5% of AML cases and gives rise to expression of the oncofusion protein CBF?-MYH11. Although different molecular mechanisms for the oncogenic activity of this fusion protein have been proposed these were mostly based on in vitro experiments or single loci analysis. Recently, we investigated the genome-wide action of this fusion protein in the context of other hematopoietic transcription factors (Mandoli et al., 2014). Here, we describe in detail the ChIP-seq and RNA-seq methods used to generate the data associated with this study. Our analysis of CBF?-MYH11 as well as multiple other hematopoietic transcription factors using ChIP-seq data revealed RUNX1 dependent binding of CBF?-MYH11 as well as interaction of the RUNX1/CBF?-MYH11 complex with other hematopoietic regulators. Further RNA-seq based analysis suggested that CBF?-MYH11 can act both as activator and repressor.

SUBMITTER: Mandoli A

PROVIDER: S-EPMC4535528 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Genome-wide binding of transcription factors in inv(16) acute myeloid leukemia.

Mandoli A A Prange K K Martens J H A JH

Genomics data 20140620

The inv(16) translocation is associated with 5% of AML cases and gives rise to expression of the oncofusion protein CBFβ-MYH11. Although different molecular mechanisms for the oncogenic activity of this fusion protein have been proposed these were mostly based on in vitro experiments or single loci analysis. Recently, we investigated the genome-wide action of this fusion protein in the context of other hematopoietic transcription factors (Mandoli et al., 2014). Here, we describe in detail the Ch ...[more]

PMID: 26484088

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Project description:Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one of the most frequently expressed antigens across AML subtypes. To better understand its potential to act as a target for immunotherapy and a biomarker for AML survival, we examined the protein and pathways that BIRC5 interacts with using the Kyoto Encyclopedia of Genes and Genomes (KEGG), search tool for recurring instances of neighbouring genes (STRING), WEB-based Gene Set Analysis Toolkit, Bloodspot and performed a comprehensive literature review. We then analysed data from gene expression studies. These included 312 AML samples in the Microarray Innovations In Leukemia (MILE) dataset. We found a trend between above median levels of BIRC5 being associated with improved overall survival (OS) but this did not reach statistical significance (p = 0.077, Log-Rank). There was some evidence of a beneficial effect in adjusted analyses where above median levels of BIRC5 were shown to be associated with improved OS (p = 0.001) including in Core Binding Factor (CBF) patients (p = 0.03). Above median levels of BIRC5 transcript were associated with improved relapse free survival (p < 0.0001). Utilisation of a second large cDNA microarray dataset including 306 AML cases, again showed no correlation between BIRC5 levels and OS, but high expression levels of BIRC5 correlated with worse survival in inv(16) patients (p = 0.077) which was highly significant when datasets A and B were combined (p = 0.001). In addition, decreased BIRC5 expression was associated with better clinical outcome (p = 0.004) in AML patients exhibiting CBF mainly due to patients with inv(16) (p = 0.007). This study has shown that BIRC5 expression plays a role in the survival of AML patients, this association is not apparent when we examine CBF patients as a cohort, but when those with inv(16) independently indicating that those patients with inv(16) would provide interesting candidates for immunotherapies that target BIRC5.

Dataset Information

Genome-wide binding of transcription factors in inv(16) acute myeloid leukemia.

Publications

Genome-wide binding of transcription factors in inv(16) acute myeloid leukemia.

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