Biology subjects

Kong, I. Y.

Publications and source records attributed to Kong, I. Y..

4 recordsLinked to original sources

bioRxiv2026

The HUSH Complex Dictates EBV-transformed B cell Sensitivity to NK Cell Surveillance Through Repression of NKG2A Ligand γ-Proto-cadherin

Natural Killer (NK) cells control Epstein-Barr virus (EBV), though how EBV+ B-cells escape NK surveillance to form tumors remains unknown. To gain insights, we performed a human genome-wide CRISPR-Cas9 screen in EBV-transformed lymphoblastoid cell lines (LCL). This revealed that the HUSH complex maintains LCL sensitivity to NK. HUSH knockout (KO) de-repressed LCL protocadherin gamma (PCDHG), typically expressed by neurons. PCDHG expression protected LCLs from NK and was necessary for HUSH KO-driven NK resistance. CRISPR analyses revealed NKG2A/CD94 as the PCDHG NK inhibitory counter-receptor, and NKG2A KO restored NK lysis of HUSH KO LCLs. HUSH perturbation impaired NK control of murine LCL xenografts in vivo. A subset of follicular lymphoma (FL) upregulate PCDHG, and PCDHG KO enhanced FL lysis by NK. Therefore, HUSH plays dual roles in foreign DNA surveillance and in support of NK, potentially as a neuronal dont kill me signal that can be exploited by transformed cells.

immunology↗

bioRxiv2025

Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Stenberg cells reveals escape from NK cell recognition and an unfolded protein response

The mutational profile of classic Hodgkin lymphoma (cHL) overlaps with that of related B cell lymphomas, including primary mediastinal B cell lymphoma (PMBL), and yet these are different histologically and clinically. To discover the molecular features that distinguish cHL, we deployed flow cytometric cell sorting and low-input RNA sequencing to generate full transcriptome data from viable, isolated Hodgkin and Red-Sternberg (HRS) cells from eighteen primary tumors, alongside matched intra-tumoral non-neoplastic B cells and four cell lines. Comparison of HRS cells to normal cellular subsets revealed evidence of abortive plasma cell differentiation, with an unfolded protein response signature, shared with plasma cell neoplasms, but not other B-cell lymphoma types. Comparison of cHL to PMBL revealed similarities but also key differences in B cell differentiation programs accompanied by upregulation of genes involved in microtubule cytoskeleton organization in cHL, which may be related to the unique multinucleated nature of HRS cells. In HRS cells, we also observed a downregulation of SLAM family receptors, which are crucial for NK cell activation, providing a potential mechanism for immune evasion from NK-mediated killing. STATEMENT OF SIGNIFICANCEThis study defines a unique transcriptional program in classic Hodgkin Lymphoma (cHL) marked by oncogenic signaling, chromatin integrity, DNA repair, and immune escape including loss of NK-activating receptors. HRS cells resemble plasma cells and have an unfolded protein response signature, which distinguishes them from diffuse large and primary mediastinal B cell lymphomas.

cancer biology↗

bioRxiv2023

Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice

Cell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we show via the direct comparison of mice genetically deficient in apoptotic caspase-8 in myeloid cells, or the essential necroptotic regulators, Receptor-interacting protein kinase-3 (RIPK3) and Mixed lineage kinase domain-like (MLKL), that RIPK3-caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and NAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and NAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport and metabolism and, congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease.

immunology↗

bioRxiv2022

RNA decay defines the therapeutic response to transcriptional perturbation in cancer

Therapeutic targeting of dysregulated transcriptional programs has arisen as a promising strategy for the treatment of leukaemias. The therapeutic response to small molecule inhibitors of Bromodomain-Containing Proteins (BRD), such as BRD2 and BRD4, P300/cAMP-response element binding protein (CBP) and Cyclin Dependent Kinases (CDKs), is generally attributed to the selective disruption of oncogenic gene expression networks driven by enhancers, super-enhancers (SEs) and lineage-specific transcription factors (TFs), including the c-MYC oncogene. Using technologies such as thiol (SH)-linked alkylation for the metabolic sequencing of RNA sequencing (SLAM-seq) to profile messenger RNA (mRNA) decay and production rates, we demonstrate that gene intrinsic properties largely govern the selectivity associated with transcriptional inhibition, where total mRNA response signatures are dominated with genes that have short transcript half-lives, including those regulated by SEs and oncogenic TFs. Further highlighting that gene sensitivities only occur in the context of short transcript half-lives, stabilisation of the c-MYC transcript through changes in the 3 UTR rendered it insensitive to transcriptional targeting. However, this was not sufficient to rescue c-MYC target gene transcription and anti-leukaemia effects following transcriptional inhibition. Importantly, long-lived mRNAs encoding essential genes that evade transcriptional targeting can be rendered sensitive via modulation of mRNA decay kinetics through inhibition of the RNA Binding Protein (RBP), ELAV Like RNA binding protein 1 (ELAVL1)/ Human Antigen R (HuR). Taken together, these data demonstrate that mRNA decay shapes the therapeutic response to transcriptional perturbation and can be modulated for novel therapeutic outcomes using transcriptional agents in leukaemia.

cancer biology↗