Jung-Hyun Kim

Antibody-based therapeutics targeting tumor surface markers have transformed cancer treatment; however, their efficacy is frequently limited by tumor escape mechanisms such as antigen loss, phenotypic switching, and heterogeneous target expression. Beyond genetic or transcriptional changes, RNA alternative splicing (AS) has emerged as a central post-transcriptional mechanism driving antigenic diversity and immune escape. This review outlines how AS-generated isoforms remodel surface antigen structure and function across key therapeutic targets—including CD/19/CD20/CD22, EGFR/HER2, VEGF, and PD-1/PD-L1—thereby promoting resistance to monoclonal antibodies, antibody–drug conjugates, and immune checkpoint inhibitors. The aberrant activity of splicing regulators disrupts canonical exon selection, leading to altered receptor signaling or the secretion of soluble decoy isoforms that evade immune recognition. Emerging therapeutic strategies aim to counteract these processes through antisense oligonucleotide-mediated splicing correction, pharmacologic modulation of splicing regulators, and isoform-selective antibody or CAR-T designs. Collectively, understanding splicing-driven antigenic plasticity reveals an additional, dynamic layer of resistance regulation and provides a framework for developing RNA-informed precision antibody therapies designed to restore antigen expression, overcome immune escape, and enhance durable clinical responses.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) therapy is beneficial for epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI)‐resistant non‐small cell lung cancer (NSCLC); however, the resistance mechanisms are not fully understood. In this study, we conducted a single‐cell RNA‐sequencing analysis of EGFR‐TKI‐resistant NSCLC patients grouped into ABCP responders and non‐responders. VEGFA was overexpressed in ABCP responders, whereas VEGFC was upregulated in non‐responders. VEGFA and VEGFC had exclusive distributions and interactions, suggesting their distinct roles. VEGFA facilitated the proliferation of responder tumor subcluster cells, whereas VEGFC secreted from non‐responder tumor cells interacted with tumor microenvironment cells. VEGFC predominantly cooperated with drug resistance pathways such as fibroblast growth factor signaling and YAP‐TAZ regulation, whereas VEGFA coordinated several oncogenic signaling pathways. VEGFC expression was the most significant prognostic marker (hazard ratio, 1.8 [95% confidence interval, 1.1–3.0], p = 0.015). Both VEGFA and VEGFC inhibition effectively suppressed tumor growth, suggesting that VEGF signaling complexity hampers the response to ABCP. In conclusion, combinatorial targeting of both ligands (VEGFA and VEGFC) or their receptors (VEGFR2 and KDR) may enhance the clinical benefit of ABCP in EGFR‐TKI‐resistant NSCLC patients.

Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli ( Apc ) inactivation. Mechanistically, HMGA1 “opens” chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation , illuminating HMGA1 as a potential therapeutic target in colon cancer.

Background In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer. Methods SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding. Results SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo. Conclusion We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency ( Son ^+/– ) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son ^+/– mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son ^+/– mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifted cell fate more toward the myeloid lineage but compromised lymphoid lineage development by reducing genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency caused inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.

Zhu–Tokita–Takenouchi–Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by hyperactive JAK/STAT signaling and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). However, mechanisms driving progression remain elusive and outcomes are poor after transformation. The High Mobility Group A1 (HMGA1) gene encodes chromatin regulators which are enriched in normal stem cells and aberrantly overexpressed in diverse, refractory tumors. Hmga1 also drives clonal expansion and leukemogenesis in transgenic mice when overexpressed in lymphoid cells. To investigate HMGA1 in MPN, we compared gene expression in CD34⁺ stem and progenitors from MPN patients and healthy controls. HMGA1 is overexpressed in MPN, with highest levels after transformation to MF or AML. To assess HMGA1 function in MPN progression, we silenced HMGA1 gene expression in two cell lines derived from patients with JAK2^V617F mutant MPN after transformation to leukemia. Strikingly, silencing HMGA1 disrupts cell cycle progression, proliferation, and clonogenicity in vitro while preventing leukemia engraftment in immunodeficient mice. To assess HMGA1 in more indolent disease, we crossed a JAK2^V617F mouse model of chronic MPN to an Hmga1 deficient background. Loss of one Hmga1 allele was sufficient to prevent progression to MF. Further, Hmga1 heterozygosity mitigates thrombocytosis and splenomegaly, while preventing expansion in long-term HSC, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors. Hmga1 heterozygosity also prolongs survival in a JAK2^V617F murine model of fulminant leukemia and early mortality. To define mechanisms underlying HMGA1 in MPN progression, we performed RNA sequencing in human MPN- AML cell lines and identified HMGA1-dependent transcriptional networks involved in cell fate decisions and cell cycle progression, including the master regulator gene, GATA-2. Mechanistically, HMGA1 occupies a developmental GATA-2 enhancer (+9.5) and recruits active histone marks (H3K4me1, H3K4me3) to increase GATA-2 expression. Silencing GATA-2 recapitulates the anti-leukemia phenotypes observed with HMGA1 silencing while GATA-2 re-expression partially rescues pro-leukemogenic phenotypes that occur in MPN-AML cells after HMGA1 depletion. In matched, primary peripheral blood monocytes from patients with MF, HMGA1 and GATA-2 are co-expressed and both become markedly up-regulated after transformation to AML. Epigenetic drugs predicted to target HMGA1 transcriptional networks synergize with JAK inhibitors to disrupt proliferation in MPN-AML cells. Together, our studies reveal a new paradigm whereby HMGA1 up-regulates GATA-2 to drive leukemic transformation in MPN and illuminate HMGA1 networks as novel therapeutic targets required for MPN progression. Citation Format: Liping Li, Jung-Hyun Kim, Wenyan Lu, Donna Marie Williams, Lingling Xian, Joseph Kim, Ophelia Rogers, Raajit K. Rampal, Richard P. Koche, Leslie Cope, Karen Reddy, Daniel R. Matson, Joe Zhao, Jerry L. Spivak, Alison R. Moliterno, Linda Resar. HMGA1: An epigenetic switch required for MPN progression by inducing GATA-2 and cell cycle progression through enhancer rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2666.