Biology subjects

Mansour, M. R.

Publications and source records attributed to Mansour, M. R..

3 recordsLinked to original sources

bioRxiv2025

The TARZN complex binds de novo enhancer mutations and promotes oncogenic expression in T-ALL

TAL1 is overexpressed in 40-60% of T-cell acute lymphoblastic leukemia (T-ALL) cases and forms an oncogenic core regulatory circuit (CRC) with other transcription factors such as LMO1, LMO2 and GATA3. In 5% of T-ALL cases an insertion of a consensus GT dinucleotide (MuTE) is observed upstream of the TAL1 gene, driving TAL1 overexpression. Using an in vitro reconstitution DNA pull-down assay combined with quantitative mass spectrometry, we identified proteins that preferentially bound to the MuTE sequence and demonstrated that among the candidates the RNA methyltransferase TARBP1 and the zinc finger proteins ZBTB2, ZBTB25 and ZNF639 form a complex that we term TARZN. Interestingly, the TARZN complex also bound to de novo super enhancer sites upstream of the LMO1 and LMO2 genes in T-ALL cells, indicating a putative common mechanism between these different non-coding driver mutations. Furthermore, knock-down of all TARZN members resulted in lower TAL1 protein expression in MuTE-positive but not in MuTE-negative T-ALL cells. Given TARZNs methyltransferase activity and the lack of concomitant TAL1 mRNA level changes, we investigated reduced TAL1 translation and identified reduced neo-synthesised TAL1 protein levels upon TARBP1 knockdown. Overall, these data suggest that the TARZN complex promotes oncogenic expression in T-ALL via co-transcriptional RNA methylation.

cell biology↗

bioRxiv2024

Genesis: A Modular Protein Language Modelling Approach to Immunogenicity Prediction

Neoantigen immunogenicity prediction is a highly challenging problem in the development of personalised medicines. Low reactivity rates in called neoantigens result in a difficult prediction scenario with limited training datasets. Here we describe Genesis, a modular protein language modelling approach to immunogenicity prediction for CD8+ reactive epitopes. Genesis comprises of a pMHC encoding module trained on three pMHC prediction tasks, an optional TCR encoding module and a set of context specific immunogenicity prediction head modules. Compared with state-of-the-art models for each task, Genesis encoding module performs comparably or better on pMHC binding affinity, eluted ligand prediction and stability tasks. Genesis outperforms all compared models on pMHC immunogenicity prediction (Area under the receiver operating characteristic curve=0.619, average precision: 0.514), with a 7% increase in average precision compared to the next best model. Genesis shows further improved performance on immunogenicity prediction with the integration of TCR context information. Genesis performance is further analysed for interpretability, which locates areas of weakness found across existing immunogenicity models and highlight possible biases in public datasets.

bioinformatics↗

bioRxiv2024

Focal Deletions of a Promoter Tether Activate the IRX3 Oncogene in T Cell Acute Lymphoblastic Leukemia

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that promoter tethering of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

cancer biology↗