Biology subjects

Hengst, J.

Publications and source records attributed to Hengst, J..

3 recordsLinked to original sources

bioRxiv2026

Oncofetal RNA-binding proteins of IGF2BP family suppress IRF-3 and NF-kB dependent transcription downstream of cytosolic RNA sensors

Activation of innate inflammatory signaling and tumor-specific antigen presentation in cancer cells provides a foundation for anti-cancer immunotherapies. Here, we show that the insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3), which are upregulated across diverse human malignancies, including acute myeloid leukemia (AML), suppress RNA-sensing pattern recognition receptor signaling and downstream ISRE-and NF-{kappa}B-dependent transcription. Among these pathways, RIG-I signaling is particularly sensitive to IGF2BP-mediated inhibition. This suppressive effect is strongest when all three IGF2BP paralogs are co-expressed, especially in embryonic-like hematoendothelial cells and leukemia stem cells. Mechanistically, IGF2BPs suppress innate immune signaling by directly binding to TNFAIP3 mRNA and promoting its expression. Consequently, inhibition of IGF2BPs activates innate immune signaling and induces MHC class I gene expression in AML cells, highlighting IGF2BPs as promising therapeutic targets to enhance RIG-I- and TLR-based cancer immunotherapies. HighlightsO_LIIGF2BP family of proteins regulate PRR responses C_LIO_LIIGF2BP levels affect chromatin accessibility and pan-transcriptome C_LIO_LISV40 large T antigen induces de novo expression of IGF2BPs C_LIO_LITNFAIP3 mRNA levels and stability are regulated by IGF2BPs C_LI

cancer biology↗

bioRxiv2025

CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins

Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/696284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@6a902forg.highwire.dtl.DTLVardef@2028f5org.highwire.dtl.DTLVardef@160fd4dorg.highwire.dtl.DTLVardef@95da53_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Critical roles of Ikaros and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

The IKZF1 gene encodes IKAROS - a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which Ikaros exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of Ikaros and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel Ikaros and HDAC1 functions in T-ALL: Both Ikaros and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by Ikaros is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and Ikaros-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of Ikaros and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

bioinformatics↗