Biology subjects

Bayley, R.

Publications and source records attributed to Bayley, R..

3 recordsLinked to original sources

bioRxiv2025

MYBL2 maintains stemness and promotes theta-mediated end joining in triple negative breast cancer

Triple negative breast cancer (TNBC) has a poor prognosis due to limited treatment options and high metastasis risk. Breast cancer (BC) stem/progenitor cells, also known as tumour initiating cells, are a small, difficult to target population within the tumour responsible for metastasis and therapy resistance. MYBL2 overexpression is commonly linked to poor prognosis and metastasis but its role in BC stem/progenitor cells remains elusive. To determine the role of MYBL2 in BC stem/progenitor cells we generated TNBC cell lines with inducible MYBL2 downregulation. Our findings reveal that elevated MYBL2 is essential for self-renewal, DNA repair, and replication stress response in these cells and lowering MYBL2 impairs stemness and self-renewal both in vitro and in vivo. Accordingly, our functional and mechanistic analyses indicate that high-MYBL2 stem/progenitor cells exhibit increased sensitivity to Pol{theta} inhibitors which is lost upon MYBL2 downregulation due to transcriptional suppression. Combining Pol{theta} inhibitors with ATR inhibitors further enhances this sensitivity, in vitro and ex vivo. This study thus identifies Pol{theta}/ATR inhibition as a synthetic lethality strategy to eradicate BC stem/progenitor cells and underscores MYBL2 expression as a biomarker for patient stratification in this treatment.

cancer biology↗

bioRxiv2024

SETD1A-dependent EME1 transcription drives PARPi sensitivity in HR deficient tumour cells

BackgroundCells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death and determined the mechanisms responsible. MethodsWe used cervical, breast, lung and ovarian cancer cells bearing mutations in BRCA1 or ATM and depleted SETD1A using siRNA or CRISPR/Cas9. We assessed the effects of the PARPi Olaparib on cell viability, homologous recombination, and DNA repair. We assessed underlying transcriptional perturbations using RNAseq. We also used data from The Cancer Genomics Atlas (TCGA) to investigate overall patient survival. ResultsLoss of SETD1A from both BRCA1-deficient and ATM-deficient cancer cells was associated with resistance to Olaparib, explained by an partial restoration of homologous recombination. Mechanistically, SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with sensitivity to Olaparib in these cells. Accordingly, when SETD1A or EME1 was lost, BRCA1 or ATM-mutated cells became resistant to Olaparib, and homologous recombination was partially restored. ConclusionsLoss of SETD1A or EME1 may explain why patients develop resistance to PARP inhibitors in the clinic.

cancer biology↗

bioRxiv2023

A heterozygous CEBPA mutation disrupting the bZIP domain causes MDS disease progression

Myelodysplastic syndrome disease (MDS) has a variable risk for progression to AML. Mutations in CEBPA are associated with a high risk of disease progression, but whether this mutation is causative for AML development is unclear. To answer this question, we generated patient-derived, MDS-specific iPSCs recapitulating the patient disease phenotype upon differentiation to blood, with hematopoietic progenitor cells showing erythroid and myeloid-dysplasia. Introduction of a frameshift mutation affecting the C/EBP bZIP domain led to disease progression, with a reduction in clonogenic potential, block in granulocyte development and increased self-renewal capacity of erythroid progenitors. ATAC-seq revealed that the acquisition of this mutation reshaped the chromatin landscape at distal cis-regulatory regions, promoting changes in clonal composition as observed by single cell RNAseq. Our work identifies mutant CEBPA as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies. HighlightsO_LIDevelopment of isogenic iPSC model of clonal evolution of MDS C_LIO_LIMonoallelic disruption of CEBPA bZIP domain is causative for MDS disease progression C_LIO_LIMonoallelic disruption of CEBPA bZIP reshapes chromatin landscape C_LIO_LIPatient derived iPSCs recapitulate drug responsiveness C_LI

cancer biology↗