Biology subjects

Ghule, P.

Publications and source records attributed to Ghule, P..

3 recordsLinked to original sources

bioRxiv2026

Acute degron-mediated RUNX1 loss reprograms enhancer activity to epigenetically drive epithelial destabilization and initiate cancer hallmarks

The RUNX1 transcription factor mediates cell-type specific gene expression. RUNX1 suppression and perturbations are recurrently associated with breast tumor initiation and progression. However, the mechanisms governing the dual roles of RUNX1 in sustaining the mammary epithelial phenotype while epigenetically suppressing initiation of cancer-compromised gene expression are poorly understood. To address this, we used the power of degron-mediated acute, selective, and complete RUNX1 ablation in human mammary epithelial cells. RUNX1 mediates promoter and distal enhancer-driven expression of a gene cohort. Dynamic epigenomic responsiveness upon RUNX1 ablation reveals a rapid and selective decrease in chromatin accessibility and H3K27ac at RUNX1-bound enhancers, but not promoters. While differentially initiated and expressed genes contacted by RUNX1-bound enhancers are enriched in pathways involved in epithelial maintenance and stemness, genes with RUNX1-promoter occupancy support DNA damage responsiveness. Modified cell morphology, metabolic control, increased breast cancer stemness, plasticity, anchorage-independent survival, chemoresistance, and perturbed DNA damage reactivity are observed upon RUNX1 ablation. Together, these findings define RUNX1 as an epigenetic tumor suppressor that maintains epithelial cell state by preserving enhancer activity and preventing gene expression associated with hallmarks of cancer.

cancer biology↗

bioRxiv2025

IKAROS Gene Regulatory Network Reveal ERG as a Vulnerability in B-cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is driven by transcriptional dysregulation that impairs B-cell differentiation and sustains leukemic growth. A defining feature of high-risk B-ALL is mutations in IKZF1, which encodes the tumor suppressor IKAROS. Here, we map IKAROS gene regulatory networks in IKZF1-mutated Ph B-ALL using an inducible IKAROS system and multi-omic profiling. IKAROS restoration reprograms chromatin accessibility and transcriptional control, shifting regulation from an ETS-dominated state to one enriched for B-cell lineage factors. Among repressed transcription factors, we identify ERG as a key regulatory node directly bound and antagonized by IKAROS. IKAROS binds regulatory elements near ERG and other progenitor-associated genes, coinciding with reduced ERG expression and repression of transcriptional programs linked to early B-cell developmental stages. Analysis of single-cell multiome data from human B-cell progenitors shows that ERG and IKAROS have opposing stage-specific activities and identifies a developmental stage-specific regulatory region in ERG intron 3 which is bound by IKAROS, and functionally important for ERG gene expression. Functional assays using CRISPRi and ETS inhibitors, along with gene dependency data from DepMap, confirm ERG dependency in IKZF1-deficient B-ALL. Our findings identify ERG as a context-specific dependency in IKZF1-deficient B-ALL, providing a mechanistic basis for the observed mitigation of poor prognosis for IKZF1-mutation in patients with co-occurring ERG deletions.

cancer biology↗

bioRxiv2023

Tumor microenvironmental determinants of high-risk DCIS progression

ABSTRACT/SUMMARYDuctal carcinoma in situ (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS. All patients had DCIS lesions >5cm in size with at least one additional high-risk feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, the presence of comedonecrosis, or a palpable mass. The tumor immune microenvironment was characterized using multiplex immunofluorescence to identify immune cells and their spatial relationships within the ducts and stroma. Gene copy number analysis and whole exome DNA sequencing identified the mutational burden and driver mutations, and quantitative whole-transcriptome/gene expression analyses were performed. There was no association between the percent of the DCIS genome characterized by copy number variants (CNAs) and recurrence events (DCIS or invasive). Mutations, especially missense mutations, in the breast cancer driver genes PIK3CA and TP53 were common in this high-risk DCIS cohort (47% of evaluated lesions). Tumor infiltrating lymphocyte (TIL) density was higher in DCIS lesions with TP53 mutations (p=0.0079) compared to wildtype lesions, but not in lesions with PIK3CA mutations (p=0.44). Immune infiltrates were negatively associated with hormone receptor status and positively associated with HER2 expression. High levels of CD3+CD8-T cells were associated with good outcomes with respect to any subsequent recurrence (DCIS or invasive cancer), whereas high levels of CD3+Foxp3+ Treg cells were associated with poor outcomes. Spatial proximity analyses of immune cells and tumor cells demonstrated that close proximity of T cells with tumor cells was associated with good outcomes with respect to any recurrence as well as invasive recurrences. Interestingly, we found that myoepithelial continuity (distance between myoepithelial cells surrounding the involved ducts) was significantly lower in DCIS lesions compared to normal tissue (p=0.0002) or to atypical ductal hyperplasia (p=0.011). Gene set enrichment analysis identified several immune pathways associated with low myoepithelial continuity and a low myoepithelial continuity score was associated with better outcomes, suggesting that gaps in the myoepithelial layer may allow access/interactions between immune infiltrates and tumor cells. Our study demonstrates the immune microenvironment of DCIS, in particular the spatial proximity of tumor cells and T cells, and myoepithelial continuity are important determinants for progression of disease.

cancer biology↗