Biology subjects

Radsak, M. P.

Publications and source records attributed to Radsak, M. P..

3 recordsLinked to original sources

bioRxiv2025

The Deacetylases HDAC1 and HDAC2 Safeguard BCR-ABL-positive Cells from Replication Stress-Induced Apoptosis via the Nuclear to Mitochondrial p73-NOXA Axis

Histone deacetylases (HDACs) are key epigenetic regulators that are frequently dysregulated in cancer cells. Context-specific dependencies of tumor cell survival on HDACs and the mechanisms through which HDACs determine cell stress responses by specific oncogenic pathways remain to be understood. Here we unravel how the class I deacetylases HDAC1 and HDAC2 control the fate of chronic myeloid leukemia (CML) cells undergoing DNA replication stress. Compared to normal myeloid cells (n=690), CML cells overexpress HDAC1 and HDAC2 (n=234-274). We reveal that HDAC1 and HDAC2 protect cultured and primary CML cells with the hyperactive BCR-ABL tyrosine kinase from programmed cell death through apoptosis upon DNA replication stress. Using transcriptomics and genetically defined knockdown and knockout model systems, we demonstrate that these effects depend on the transcription factor p73 and its pro-apoptotic target gene NOXA. Upon DNA replication stress, p73 binds to the NOXA promoter but only upon additional inactivation of HDAC1/HDAC2 the NOXA gene becomes transcribed. BCR-ABL translocate to the nucleus to catalyze p73 phosphorylation at tyrosine-99 for the induction of p73 and mitochondrial NOXA. Thus, the BCR-ABL oncogene creates a selective vulnerability to HDAC1/HDAC2 inhibitors, driving a cytotoxic shift in replication stress responses towards apoptosis. These data highlight HDAC1/HDAC2 as potential therapeutic targets in CML. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/694110v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1ec0c51org.highwire.dtl.DTLVardef@1cd759org.highwire.dtl.DTLVardef@17e29a8org.highwire.dtl.DTLVardef@1e0fb50_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Characterization of the TREM-1 Signaling Landscape in Human Neutrophils

The Triggering Receptor Expressed on Myeloid Cells (TREM)-1 is a member of the Immunoglobulin superfamily, and an activating receptor mainly expressed on myeloid cells. Beyond its role in acute and chronic inflammatory processes, TREM-1 is also involved in cancer emergence and progression probably by alteration of the tumor-associated neutrophils (TAN) and macrophages (TAM). Advanced information about the TREM-1 signaling cascade may reveal novel targets for treating inflammatory and cancer diseases. As many specific kinase inhibitors are approved for treating various diseases, targeting kinases being active after TREM-1 ligation serves as a promising approach. Therefore, we investigated the protein tyrosine kinome (PTK) and serine threonine kinome (STK) by kinome activity profiling of purified human neutrophils after TREM-1 activation. As TREM-1 interacts with Toll-like receptor (TLR) 4 signaling, we used TLR4-activation by LPS to define TREM-1 specific pathways. We found an increased kinome activity after receptor ligation and could predict individual kinases. To gain further insights into the signaling cascade, we additionally investigated the transcriptomic profile that made us available to link the kinome activity to the resulting transcriptomic profile. In sum, we revealed several signaling pathways being active after TREM-1 ligation that are associated with various biological processed and diseases. This study facilitates selecting kinase inhibitors for further validation with the aim of targeting TREM-1 signaling in various inflammatory or cancer disease conditions.

immunology↗

bioRxiv2022

Immunomodulation of Neutrophil Granulocyte Functions by Bacterial Polyphosphates

Polyphosphates are highly conserved, linear polymers of monophosphates that reside in all living cells. Bacteria produce long chains containing hundreds to thousands of phosphate units, which can interfere with host defense to infection. Here, we report that intratracheal long-chain polyphosphate administration to C57BL/6J mice resulted in the release of proinflammatory cytokines and influx of Ly6G+ polymorphonuclear neutrophils in the bronchoalveolar lavage fluid causing a disruption of the physiologic endothelial-epithelial small airway barrier and histologic signs of lung injury. Polyphosphate-induced effects were attenuated after neutrophil depletion in mice. In isolated murine neutrophils, long-chain polyphosphates modulated cytokine release induced by lipopolysaccharides (LPS) from gram-negative bacteria or lipoteichoic acid from gram-positive bacteria. In addition, long-chain polyphosphates induced immune evasive effects in human neutrophils. In detail, long-chain polyphosphates down-regulated CD11b and curtailed the phagocytosis of E. coli particles by neutrophils. Polyphosphates modulated the migration capacity by inducing CD62L shedding resulting in CD62Llow and CD11blow neutrophils. The release of IL-8 induced by LPS was also significantly reduced. Pharmacologic blockade of PI3K with wortmannin antagonized long-chain polyphosphate-induced effects on LPS-induced IL-8 release. In conclusion, polyphosphates govern immunomodulation in murine and human neutrophils suggesting polyphosphates as a therapeutic target for bacterial infections to restore innate immune defense.

immunology↗