Biology subjects

Kridel, R.

Publications and source records attributed to Kridel, R..

4 recordsLinked to original sources

bioRxiv2025

Multidimensional characterization of cellular ecosystems in Hodgkin lymphoma

The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

cancer biology↗

bioRxiv2025

Blood-based Epigenetic Instability Linked to Human Aging and Disease

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation--where a pattern considered abnormal in one cell type may be normal in another--poses challenges in identifying methylation abnormalities linked to disease risk. Through genome-wide analyses, we identified CpG sites with remarkably consistent methylation profiles in healthy whole blood, predominantly existing in an unmethylated state. We examined alterations at these epigenetically stable loci in diverse cohorts, including those with cardiovascular disease and hematological cancers. Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden fluctuations during leukemia treatment. In non-cancer cohorts, we observed that normally stable CpG sites exhibited progressive instability with advancing age, which was also associated with the onset of cardiovascular disease and decreased survival rates. This study links DNA methylation instability with the expansion of risk-prone blood cells and highlights its role as a biomarker for both cancer and cardiovascular disease.

genetics↗

bioRxiv2023

Simulating cell-free chromatin using preclinical models for cancer-specific biomarker discovery

Cell-free chromatin (cf-chromatin) is a rich source of biomarkers across various conditions, including cancer. Tumor-derived circulating cf-chromatin can be profiled for epigenetic features, including nucleosome positioning and histone modifications that govern cell type-specific chromatin conformations. However, the low fractional abundance of tumor-derived cf-chromatin in blood and constrained access to plasma samples pose challenges for epigenetic biomarker discovery. Conditioned media from preclinical tissue culture models could provide an unencumbered source of pure tumor-derived cf-chromatin, but large cf-chromatin complexes from such models do not resemble the nucleosomal structures found predominantly in plasma, thereby limiting the applicability of many analysis techniques. Here, we developed a robust and generalizable framework for simulating cf-chromatin with physiologic nucleosomal distributions using an optimized nuclease treatment. We profiled the resulting nucleosomes by whole genome sequencing and confirmed that inferred nucleosome positioning reflected gene expression and chromatin accessibility patterns specific to the cell type. Compared with plasma, simulated cf-chromatin displayed stronger nucleosome positioning patterns at genomic locations of accessible chromatin from patient tissue. We then utilized simulated cf-chromatin to develop methods for genome-wide profiling of histone post-translational modifications associated with heterochromatin states. Cell-free chromatin immunoprecipitation and sequencing (cf-ChIP-Seq) of H3K27me3 identified heterochromatin domains associated with repressed gene expression, and when combined with H3K4me3 cfChIP-Seq revealed bivalent domains consistent with an intermediate state of transcriptional activity. Combining cfChIP-Seq of both modifications provided more accurate predictions of transcriptional activity from the cell of origin. Altogether, our results demonstrate the broad applicability of preclinical simulated cf-chromatin for epigenetic liquid biopsy biomarker discovery.

genomics↗

bioRxiv2017

DNA copy number gains of TCF4 (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin- (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target the TCF4 (E2-2) transcription factor, and that over-expression of TCF4 leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. The TCF4 gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killed in vitro and in vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

genomics↗