Biology subjects

Aydemir, I.

Publications and source records attributed to Aydemir, I..

3 recordsLinked to original sources

bioRxiv2026

Stromal Gasdermin D-mediated Pyroptosis Drives Maladaptive CD4⁺ T-cell Remodeling in Tet2-Deficient Hematopoiesis

An inflammatory bone marrow microenvironment is increasingly recognized as critical in myeloid disease evolution, yet how stromal inflammation interfaces with adaptive immunity remains poorly defined. Here, we show that stromal pyroptosis drives mutation-specific myeloid expansion by coordinating monocytic remodeling and CD4 T-cell activation. Genetic ablation of gasdermin D in the bone marrow stroma suppressed stromal pyroptosis and attenuated Tet2-deficient myeloid expansion. Tet2 deficiency skewed monocyte and macrophage differentiation toward an activated, antigen-presenting state that interacted with pyroptotic stromal cells to promote expansion of a distinct CD4 T-cell population. These cells expressed canonical T follicular helper markers (Bcl6, Cxcr5, Il21, and Cd40l) together with interferon-responsive and tissue-interaction programs, consistent with an inflammation-adapted TFH-like state. CD40L produced by these cells reinforced the expansion of Tet2-deficient monocytes and macrophages, establishing a feed-forward stromal-immune circuit. Disruption of this axis through stromal gasdermin D deficiency or CD40L blockade attenuated myeloid expansion in vivo. Consistent with these findings, patients with isolated TET2 loss-of-function mutations exhibited CD4 T-cell skewing and CD40L+ T-cell-rich tertiary lymphoid structures in the bone marrow. Together, these data identify a pyroptosis-dependent stromal-immune axis that links early myeloid inflammation to maladaptive remodeling of adaptive immunity and reveals a context-dependent therapeutic vulnerability in Tet2-deficient hematopoiesis.

cancer biology↗

bioRxiv2026

Binary-SPA: A Reference-Free Method for Cell Annotation in High-Resolution Spatial Transcriptomics

Accurate cell type annotation remains a major challenge in high-resolution spatial transcriptomics analysis. Current approaches primarily rely on label transfer from single-cell RNA sequencing (scRNA-seq) reference datasets or marker-based annotation of transcriptionally defined clusters. While these methods are widely used, they have critical limitations. Label transfer approaches depend on the availability of a well-matched scRNA-seq reference. Marker-based annotation methods often suffer from accuracy and limited coverage. To address these challenges, we developed Binary-SPA, a computational framework for cell-type annotation of high-resolution spatial transcriptomics data. Binary-SPA performs annotation in two stages. First, a binary classification step identifies high-confidence cells using predefined marker sets. These confidently annotated cells are then used as an internal reference for anchor-based label transfer in the second stage. Binary-SPA outperforms conventional marker-based annotation approaches and existing label transfer methods across multiple high-resolution spatial transcriptomics platforms, preservation methods, and tissue types. While label transfer methods achieve high accuracy only when same-tissue scRNA-seq references are available, and decline substantially when relying on independent datasets, Binary-SPA matches this performance with 100% annotation coverage while eliminating the need for external reference data entirely. Binary-SPA demonstrates robust performance even in challenging specimens such as bone marrow biopsies, and validation against matched COMET protein expression data confirmed strong concordance between transcriptomic- and protein-based cell identities. Binary-SPA thus provides a robust, reference-free solution for spatial transcriptomics annotation with broad applicability to research and clinical specimens.

genomics↗

bioRxiv2024

DDX41 dissolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death

Deleterious germline DDX41 variants constitute the most common inherited predisposition disorder linked to myeloid neoplasms (MNs). The role of DDX41 in hematopoiesis and how its germline and somatic mutations contribute to MNs remain unclear. Here we show that DDX41 is essential for erythropoiesis but dispensable for the development of other hematopoietic lineages. Using stage-specific Cre models for erythropoiesis, we reveal that Ddx41 knockout in early erythropoiesis is embryonically lethal, while knockout in late-stage terminal erythropoiesis allows mice to survive with normal blood counts. DDX41 deficiency induces a significant upregulation of G-quadruplexes (G4), noncanonical DNA structures that tend to accumulate in the early stages of erythroid precursors. We show that DDX41 co-localizes with G4 on the erythroid genome. DDX41 directly binds to and dissolves G4, which is significantly compromised in MN-associated DDX41 mutants. Accumulation of G4 by DDX41 deficiency induces erythroid genome instability, defects in ribosomal biogenesis, and upregulation of p53. However, p53 deficiency does not rescue the embryonic death of Ddx41 hematopoietic-specific knockout mice. In parallel, genome instability also activates the cGas-Sting pathway, which is detrimental to survival since cGas-deficient and hematopoietic-specific Ddx41 knockout mice are viable without detectable hematologic phenotypes, although these mice continue to show erythroid ribosomal defects and upregulation of p53. These findings are further supported by data from a DDX41 mutated MN patient and human iPSC-derived bone marrow organoids. Our study establishes DDX41 as a G4 dissolver, essential for erythroid genome stability and suppressing the cGAS-STING pathway.

cancer biology↗