Biology subjects

Edin, G.

Publications and source records attributed to Edin, G..

3 recordsLinked to original sources

bioRxiv2026

LncRNA-mediated organization of oncogenic chromatin state is a targetable vulnerability in leukemia

Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of gene expression underlying various cellular functions, however, the functional and mechanistic contributions of most lncRNAs to tumorigenesis remain poorly defined, and targeting of lncRNAs is challenging with conventional therapeutic approaches. Here, we uncover human PAN3-AS1 and its murine ortholog Lnc35682, previously uncharacterized lncRNAs embedded within a conserved syntenic genomic locus, as highly expressed in acute myeloid leukemia (AML). Using genetic mouse models, human cell lines and primary patient samples, we show that PAN3-AS1 is essential for leukemia maintenance but dispensable for normal hematopoiesis. Mechanistically, we find that elevated PAN3-AS1 influences chromatin accessibility, thus promoting leukemia gene expression programs. This is mediated, at least in part, by PAN3-AS1s association with the nuclear lamina through a defined functional region that is required for its leukemogenic function. We further characterize a feed-forward regulatory circuit between PAN3-AS1 and its neighboring gene FLT3 that directly links the aberrant lncRNA functions to the FLT3-mutant AML subtype. To therapeutically exploit the regulatory node, we engineer a myeloid leukemia-preferentially targeted lipid nanoparticle (LNP) formulation and demonstrate effective delivery of siRNAs against endogenous targets into leukemia cells in experimental animals. LNP-siPAN3-AS1 alone or in combination with a clinically used FLT3 inhibitor, Gilteritinib, reduces leukemia burden and significantly delay leukemogenesis in vivo. Overall, our study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744058v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@10c9d42org.highwire.dtl.DTLVardef@12864e7org.highwire.dtl.DTLVardef@f87f6aorg.highwire.dtl.DTLVardef@750cbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Loss of cell cycle gatekeeping by 1 CNOT3 impairs hematopoietic stem and progenitor cell division and repopulating activity

Adult mammalian hematopoietic stem cells (HSCs) constitute a heterogeneous population responsible for generating various cell types in the blood throughout adulthood. Gene expression programs underlying regulation of self-renewal and differentiation of HSCs are tightly regulated. However, how post-transcriptional regulation of gene expression influences HSCs and hematopoiesis remains largely unexplored. Here, we report the critical role of CNOT3, a subunit of the CCR4-NOT complex, in regulating hematopoietic stem cells (HSCs) function in adult hematopoiesis. We observed that Cnot3 mRNA is highly expressed in HSCs and CNOT3 ablation in the murine Cnot3 conditional knockout mouse model resulted in anemia, reduced bone marrow cellularity and enhanced extramedullary hematopoiesis in spleen. Deletion of Cnot3 resulted in the early expansion of immunophenotypic HSCs which were then progressively lost over time. Cnot3 knockout hematopoietic stem/progenitor cells (HSPCs) failed to reconstitute hematopoietic systems of recipient animals in transplantation assays. Single-cell RNA sequencing (scRNA-seq) analysis of HSPCs revealed disruptions in lineage development and loss of HSCs. Transcriptomic profiling and cell cycle analysis demonstrated that Cnot3 deletion led to increased cycling activity in HSCs. Our results indicate that CNOT3 is critical for maintenance of homeostasis in HSCs and the hematopoietic system.

developmental biology↗

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↗