Keon Hee Yoo

Zinc finger proteins (ZNFs) are increasingly recognized as regulators of oncogenic transcriptional networks and DNA damage responses. Through integrative analysis of bulk and single-cell RNA sequencing data, we identified a conserved set of seven ZNF genes, including ZNF184, that are upregulated in acute lymphoblastic leukemia (ALL) and exhibit dynamic expression patterns linked to disease progression. Among these, ZNF184 uniquely localized to DNA double-strand breaks (DSBs) in a zinc finger domain-dependent manner. Functional analyses revealed that ZNF184 suppresses homologous recombination (HR)-mediated DNA repair by impeding BRCA1 recruitment, leading to accumulation of DNA damage. ZNF184 expression was elevated in primary ALL samples and associated with increased γH2AX levels and inferior overall survival in ALL patients. Loss of ZNF184 restored HR efficiency, reduced DNA damage burden, and enhanced genome stability, while re-expression re-sensitized cells to DNA-damaging agents. Mechanistically, ZNF184 directly interacted with TRIM28 and facilitated its recruitment to DSBs, modulating TRIM28 phosphorylation and chromatin remodeling through the HP1/SUV39H1 complex. ZNF184 expression conferred heightened sensitivity to PARP inhibition and synergized with genotoxic chemotherapy in both cell lines and patient-derived ALL cells. These findings identify ZNF184 as a key modulator of DSB repair and a predictive biomarker for therapeutic strategies targeting HR-deficient ALL.

X-linked lymphoproliferative syndrome type 1 (XLP1) is an inborn error of immunity caused by pathogenic variants in SH2D1A and is frequently complicated by Epstein-Barr virus (EBV)–associated lymphoproliferative disorders (LPDs). However, cases of LPD without EBV infection have been reported and remain poorly understood. We investigated tumorigenesis mechanisms through transcriptomic profiling and somatic variant analysis in tumor samples from six patients with XLP1. Pathogenic variants were identified in two: one developed two distinct LPDs harboring CARD11/GNA13 and MECOM variants, while the other carried IRF4, P2RY8, KRAS, and CCND3 variants. Transcriptome analysis of three tumors, compared with diffuse large B cell lymphoma from patients without an underlying immune defect, revealed a distinct expression profile. Gene Ontology analysis showed upregulation of adaptive immune response genes, including various IgH and TCR genes, suggesting polyclonal lymphocyte proliferation. Overall, LPD associated with XLP1 may originate from polyclonal lymphocyte expansion, either in the presence or absence of EBV infection, and subsequently progress to malignancy through somatic variants.

Shin A, et al. Infect Chemother. 2026 ;58:e28. https://doi.org/10.3947/ic.2025.0158

Hyun-Young Kim, M.D., Ph.D., Boram Kim, M.D., Min-Seung Park, M.D., Ph.D., Jong-Ho Park, Ph.D., Hee Young Ju, M.D., Ph.D., Keon Hee Yoo, M.D., Ph.D., Jun Ho Jang, M.D., Ph.D., Chul Won Jung, M.D., Ph.D., and Hee-Jin Kim, M.D., Ph.D.. Ann Lab Med -0001;0:. https://doi.org/10.3343/alm.2025.0300

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by chemotherapy resistance, leading to poor patient outcomes. This study investigates the role of adaptor protein complex 2 subunit mu 1 (AP2M1) in hematopoiesis and drug response. Utilizing multimodal analyses on bone marrow samples from AML patients and healthy controls, zebrafish models, and human AML cell lines, it is identified that dysregulation of AP2M1 impairs hematopoietic stem and progenitor cell (HSPC) development, underscoring its critical role in hematopoiesis. AP2M1 expression distinctly differentiates normal from malignant cells, surpassing well‐recognized cancer stem cell markers, ATP‐binding cassette transporters, known for drug efflux and chemoresistance. Elevated AP2M1 levels in AML HSPCs correlate with poor clinical outcomes, as its overexpression reduces apoptosis, enhances stemness, and increases drug resistance. In vivo experiments reveal that AP2M1 directly modulates Notch1 expression, amplifying pro‐tumorigenic effects through the Notch1 signaling pathway. These findings highlight the pivotal role of AP2M1 in AML pathogenesis, primarily through its regulation of NOTCH1 expression and signaling cascades. These findings unravel AP2M1 as a previously unrecognized factor in AML pathogenesis and suggest a treatment strategy for AML, focusing on the AP2M1‐NOTCH1 axis.

Cytokine-Primed MSCs Enhance Antitumor Immunity-Associated Gene Expression Without Promoting AML Cell Growth

Purpose Recent treatments for pediatric acute lymphoblastic leukemia (ALL) are founded on risk stratification. We examined the survival rates and prognostic factors of patients over a 20-year period at a single institution.Materials and Methods This study analyzed patients diagnosed with ALL and treated at the Pediatric Department of Samsung Medical Center (SMC). Patients were categorized into standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. The SMC protocol for the HR group underwent two changes during the study period: a modified Children’s Cancer Group (CCG)-1882 protocol was used from 2000 to 2005, the Korean multicenter HR ALL-0601 protocol from 2006 to 2014, and the Korean multicenter HR ALL-1501 protocol from 2015 to 2019.Results Of the 460 patients, complete remission was achieved in 436 patients (94.8%). The 10-year overall survival rate (OS) was 83.8±1.9% for all patients. OS according to the SMC risk group was as follows: 95.9%±1.4% in the SR group, 83.8%±3.6% in the HR group, and 66.2%±6.9% in the VHR group. The 5-year OS within the HR group varied according to the treatment protocol: 73.9%±7.5%, in the modified CCG-1882 protocol, 83.0%±3.9%, in the 0601 protocol, and 96.2%±2.6%, in the 1501 protocol. For those aged 15 years and older, the OS was only 56.5%±13.1%. Relapse occurred in 71 patients (15.4%), and the OS after relapse was 37.7%±6.0%.Conclusion The treatment outcomes of patients with ALL improved markedly. However, there is a need to further characterize adolescents and young adult patients, as well as those who have experienced relapses.

Objectives: Despite its utility, interpreting multiparameter flow cytometry (MFC) data for hematologic malignancy remains time-intensive and complex. This study evaluated the applicability of two dimensionality reduction (DR) algorithms, t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), to MFC data of hematologic malignancy. Methods: A total of 237 samples were re-analyzed by t-SNE- and UMAP-based gating: 80 with acute leukemia orientation tube panel, 42 with B-cell lymphoma (BCL) panel, 45 with multiple myeloma (MM) panel, 40 and 30 with measurable residual disease (MRD) panels for B-cell acute lymphoblastic leukemia (B-MRD) and MM (MM-MRD), respectively. Each result was compared to the manual gating, and sensitivity and precision were assessed using BCL and B-MRD panels. Results: Compared to manual gating, DR-based gating demonstrated agreements over 95.0 % for all MFC panels, and quantitative correlations ( ρ ) exceeded 0.94. Both t-SNE- and UMAP-based gating showed a sensitivity and negative predictive value of 100 %. Also, in one sample each from the BCL and MM-MRD panels, DR-based gating identified populations that were missed by manual gating. Sensitivity evaluation showed that both t-SNE- and UMAP-based gating successfully identified MRD populations down to the lowest MRD level of 10 ^−5.30 when applying primary-gating strategy for CD19-positive population. Precision evaluation showed coefficient of variation below 10 % across all levels. Conclusions: This study shows that DR-based gating streamlines data interpretation and minimizes overlooked populations, demonstrating significant potential as a valuable tool in MFC analysis for hematologic malignancies.

Measurable residual disease (MRD) is critical in guiding therapeutic strategies for B-cell acute lymphoblastic leukemia (B-ALL). This study evaluated the performance of a novel next-generation sequencing-based Celemics IGH assay (CM-IGH; Celemics, Seoul, Korea) compared with the LymphoTrack^® IGH FR1 assay (LT-IGH; Invivoscribe Technologies, USA) and multiparameter flow cytometry (MFC). A total of 31 diagnostic and 60 follow-up bone marrow aspirate samples, all from the same 31 pediatric patients with B-ALL, were analyzed using the CM-IGH and LT-IGH assays on the MiSeq platform, as well as MFC according to EuroFlow guidelines. Initial IGH clonality was detected in 83.9% of CM-IGH samples and 90.3% of LT-IGH samples (p = 0.060). MRD positivity rates in follow-up samples were 74.5% for CM-IGH, 61.1% for LT-IGH, and 56.7% for MFC. CM-IGH showed concordance rates of 78.3% with LT-IGH and 68.1% with MFC, while LT-IGH demonstrated an 81.5% concordance rate with MFC. The correlation coefficients (r) of MRD levels were 0.831 between CM-IGH and LT-IGH, 0.702 between CM-IGH and MFC, and 0.776 between LT-IGH and MFC. The CM-IGH assay demonstrates substantial concordance with LT-IGH and MFC in detecting MRD in pediatric patients with B-ALL, highlighting the complementary value of IGH clonality assays and MFC.

Purpose Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups.Materials and Methods A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients’ disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease.Results Among the 549 screened patients, a total of 418 patients were included in the study; B-cell ALL (n=379) and T-cell ALL (T-ALL) (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher-risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.002). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.002) and OS (p=0.022) when HSCT was done as upfront treatment.Conclusion HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.