Biology subjects

Stock, W.

Publications and source records attributed to Stock, W..

4 recordsLinked to original sources

bioRxiv2023

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia.

T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of Tal1 or Lyl1 in T cell progenitors or inactivation of E2a, is sufficient to predispose mice to develop T-ALL. How E2a suppresses thymocyte transformation is currently unknown. Here, we show that early deletion of E2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion of E2a prevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2a suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymus cellularity is a determinant of leukemogenesis.

cancer biology↗

bioRxiv2023

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes. HIGHLIGHTSO_LIPro-B progenitor cells as the most common cell-of-origin for B-ALL C_LIO_LIAP-1 TF-associated cis-regulatory rewiring in B-ALL C_LIO_LISubtype-specific accessible chromatin signatures representing 20% of all B-ALL sites C_LIO_LIRole for distinct TFs in promoting subtype-specific chromatin architectures C_LIO_LIThousands of inherited genetic variants identified impacting chromatin state C_LI

cancer biology↗

bioRxiv2022

Identification of microbial exopolymer producers in sandy and muddy intertidal sediments by compound-specific isotope analysis

Extracellular polymeric substances (EPS) refer to a wide variety of high molecular weight molecules secreted outside the cell membrane by biofilm microorganisms. In the present study, EPS from marine microphytobenthic biofilms were extracted and their isotope ratios were analysed. A comparison of these ratios with the carbon isotope ratios of fatty acid biomarkers allowed the identification of the main EPS producers of two contrasting types of intertidal marine sediments. Our study reveals that EPS sources are more diverse in sandy sediments than in muddy sediments. We also found distinct patterns in the production and breakdown of EPS in sandy and muddy environments. The main difference observed was in how epipelic and epipsammic diatoms affected the chemistry of EPS, which had significant implications for the growth of bacteria specialized in utilizing EPS. These differences were likely linked to variations in the functioning of epipelic and epipsammic communities, specifically in how EPS was used either for motility or for cell attachment.

ecology↗

bioRxiv2020

Distinct genetic pathways define pre-leukemic and compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with predisposition to developing leukemia. We found that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. EIF6 mutations cause functional compensation for the germline deficiency by alleviating the SDS ribosome joining defect, improving translation, and reducing p53 activation. TP53 mutations decrease checkpoint activation without affecting ribosome assembly. We link development of leukemia with acquisition of biallelic TP53 alterations. Our results define distinct pathways of clonal selection driven by germline fitness constraint and provide a mechanistic framework for clinical surveillance.

cancer biology↗