INTRODUCTION:Concurrent atypical BCR::ABL1 transcripts and SET::NUP214 fusions are rare in chronic myeloid leukemia (CML) and may complicate disease classification and treatment decisions. METHODS:Clinical, morphologic, cytogenetic, fluorescence in situ hybridization, and next-generation sequencing findings were reviewed in a patient with de novo myeloid blast-phase CML. RESULTS:A 68-year-old man presented with hyperleukocytosis and was diagnosed with myeloid blast-phase CML harboring an atypical e13a3 BCR::ABL1 transcript and concurrent SET::NUP214 fusion. Single-agent dasatinib induced rapid remission, clearance of both fusion transcripts, and sustained molecular remission beyond 15 months. CONCLUSION:Concurrent atypical BCR::ABL1 and SET::NUP214 fusions are rare in myeloid blast-phase CML. Despite this molecular complexity, durable molecular remission was achieved with single-agent dasatinib.
Eukaryotic translation initiation factors (eIFs) play a crucial role in tumor progression; however, which eIFs are most significant in cervical cancer (CC) remains unclear. In this study, eIF3A and eIF4E were found to be highly expressed in CC and associated with poor prognosis. Silencing either factor inhibited CC cell proliferation, induced apoptosis, and reduced glycolytic activity. Quantitative proteomic analysis and subsequent functional validation identified α-enolase (ENO1) as a common downstream effector of eIF3A and eIF4E, through which they promoted aerobic glycolysis and CC progression. Notably, eIF3A consistently exhibited a more pronounced functional effect than eIF4E. Further analyses demonstrated that eIF3A associated with N6-methyladenosine (m6A)-modified ENO1 mRNA and promoted its translation. eIF3A depletion reduced the abundance of ENO1 mRNA in actively translating polysomes and decreased the ENO1 protein-to-mRNA ratio without affecting total ENO1 mRNA abundance. Mutation of a key m6A site A359 in ENO1 mRNA similarly weakened its association with eIF3A and reduced ENO1 translation. Moreover, pharmacological inhibition of m6A-related regulation partially attenuated eIF3A-induced ENO1 expression, glycolytic activation, and tumor growth. Collectively, our results identify eIF3A as a key regulator of CC progression in an m6A-dependent ENO1 translation and suggest that targeting the eIF3A-m6A-ENO1 may have therapeutic potential for CC.
Optic pathway gliomas (OPG) are a heterogeneous group of low-grade tumors that primarily affect the pediatric population and are frequently associated with neurofibromatosis type 1. Although typically low-grade, OPG can exhibit highly variable clinical behavior, ranging from asymptomatic lesions to progressive visual and neurological impairment. Recent advances in molecular biology have identified key alterations in the Mitogen-Activated Protein Kinase (MAPK) pathway, particularly involving BRAF, such as BRAFV600E variant and KIAA1549::BRAF fusions, which play a central role in tumor initiation and progression of this kind of tumors. This review synthesizes current evidence on the epidemiology, classification, molecular pathogenesis, and tumor microenvironment of OPG, emphasizing the relationship between genotype and clinical phenotype. Additionally, it examines conventional and emerging therapeutic strategies, including chemotherapy, radiotherapy, and targeted therapies such as MEK and BRAF inhibitors. Understanding the molecular drivers and immune interactions underlying OPG has enabled the development of more precise diagnostic and therapeutic approaches. However, significant gaps remain in understanding the mechanisms of progression, treatment resistance, and genotype-phenotype correlations. Future research should focus on integrating molecular biomarkers into clinical decision-making and exploring combination therapies to improve patient outcomes.
Multiple myeloma (MM) is a severe plasma-cell malignancy that continues to cause substantial morbidity and mortality despite major therapeutic advances. Although current therapies target distinct molecular processes, many patients eventually relapse, raising the question of whether diverse treatments impose different pressures that nevertheless converge on shared transcriptional adaptation programs. While many studies have profiled transcriptional changes before and after treatment, these responses are often analyzed within individual drugs, leaving recurrent programs across therapies insufficiently explored. Here, we developed PRISM-MM (Perturbation Response Inference by Sparse integrative Modeling for Multiple Myeloma), an interpretable sparse integrative dictionary-learning framework that decomposes drug-control transcriptional shifts into signed response programs while accounting for drug identity, study background and cell-source state. By incorporating paired scRNA-seq as a calibration layer, PRISM-MM preserved cell-state-level interpretability and outperformed representative perturbation-prediction models in recovering reproducible response structure. Applied to a curated multi-study MM perturbation compendium, PRISM-MM identified conserved treatment-associated programs validated in held-out bulk and external paired scRNA-seq datasets. These programs revealed a recurrent remodeling pattern characterized by depletion of plasma-cell-like secretory activity and enrichment of inflammatory, adhesion-associated and stress-tolerant immune-interface states. We further nominated state-maintaining genes and highlighted a RFXAP-centered immune-regulatory axis that may drive the Program 8 inflammatory adaptation state and shape MM drug response. Together, PRISM-MM provides an interpretable framework for discovering conserved drug-response programs and generating mechanistic hypotheses about treatment adaptation in MM.
This study aimed to investigate the clinical significance, biological function, and molecular mechanisms of MAGEA4 in the progression of gastric cancer (GC). Analysis of the TCGA database and 40 pairs of GC tissues and matched normal mucosa samples revealed that MAGEA4 expression was significantly upregulated in GC. Immunohistochemical analysis using two tissue microarrays containing 195 GC samples demonstrated that high MAGEA4 expression is significantly associated with advanced tumor stage, lymph node metastasis and unfavorable patient prognosis. Both in vitro and in vivo experiments confirmed that MAGEA4 significantly promoted the proliferation and metastasis of GC cells. Investigations of the underlying mechanisms revealed that MAGEA4 promotes GC progression by inducing chromosomal instability (CIN). This was evidenced by increased γH2AX (a sensitive DNA damage marker for double-strand breaks), abnormal chromosome numbers, abnormal mitosis, and other CIN features. At the molecular level, MAGEA4 binds E2F1 to enhance STAU1 transcription, subsequently promotes c-Myc translation and drives CIN. Knockdown of STAU1 effectively reversed the CIN and malignant phenotypes induced by MAGEA4 overexpression in GC cells, whereas overexpression of c‑Myc restores these phenotypes resulted from MAGEA4 knockdown. In summary, this research demonstrated the crucial role of MAGEA4 in promoting GC progression by inducing CIN via the E2F1/STAU1/c-Myc axis. Consequently, MAGEA4 represents a highly promising novel therapeutic target for GC.
RECQL5 is a member of the RecQ helicase family involved in DNA replication, homologous recombination, and maintenance of genomic stability. While germline pathogenic variants in other RecQ helicases cause established cancer predisposition syndromes, the role of RECQL5 in human cancer susceptibility remains uncertain. We report monozygotic adolescent twins with distinct tumors: dysembryoplastic neuroepithelial tumor in one twin and Burkitt lymphoma in the other. Clinical genome sequencing was initially nondiagnostic, but reanalysis identified a rare heterozygous nonsense variant in RECQL5 (NM_004259.7:c.2698C>T, p.(Gln900Ter)), present in both twins and their unaffected mother. The variant is predicted to undergo nonsense-mediated mRNA decay or produce a truncated protein lacking the C-terminal SRI (Set2-Rpb1 interacting) domain, which mediates interaction with RNA polymerase II. However, tumor sequencing data were not available to evaluate loss of heterozygosity or second somatic events. Given the unaffected carrier parent, lack of tumor molecular confirmation, and the biological heterogeneity of the tumors, a causal relationship for this variant cannot be established. This case highlights the challenges of interpreting rare germline variants in genes with emerging but incompletely characterized disease associations. Although the available evidence is insufficient to establish a definitive causal relationship, the identification of a shared loss-of-function RECQL5 variant in monozygotic twins with distinct tumors is noteworthy and adds to the limited clinical evidence suggesting a potential role for RECQL5 in cancer susceptibility. Additional functional studies, tumor-based analyses and the accumulation of well-characterized clinical cases will be essential to determine whether RECQL5 contributes to hereditary cancer predisposition.
BACKGROUND AND PURPOSE:Based on the assumption that radiation dose escalation to the primary tumor improves local control and therefore produces survival benefits under the condition of limiting the dose to the organ at risk (OAR), we launched a study to evaluate the effect of simultaneous integrated boost (SIB) radiotherapy implemented in stage III locally advanced non-small cell lung cancer (LA-NSCLC) patients. MATERIALS AND METHODS:A prospective, single-center, open-label, randomized phase II trial was performed in patients with stage III LA-NSCLC. Patients were randomized to receive SIB thoracic radiation: 50 Gy in 25 fractions of 2.0 Gy for planning target volume (PTV), 55 Gy in 25 fractions of 2.2 Gy for clinical target volume (CTV), 60-70 Gy in 25 fractions of 2.4-2.8 Gy for gross tumor volume (GTV), or control group: 30 fractions of 2.0 Gy for PTV. A platinum based concurrent chemotherapy was administered to patients in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), failure patterns, and treatment-related toxicities. Exploratory analyses of epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) were performed for PFS and OS. RESULTS:From April 2015 to April 2018, 168 patients were included in the analysis, with 84 in the control group and 84 in the SIB group. The median PFS was 21.0 months in the SIB group and 11.0 months in the control group (P < 0.001, Hazard Ratio (HR) 0.48, 95% CI 0.34-0.68). The median OS was 42.0 months and 26.0 months(P = 0.002, HR 0.55, 95% CI 0.37-0.81) in the SIB group and the control group, respectively. The SIB group had a significantly lower risk of brain and other distant metastasis, with adjusted sub-distribution HR of 0.35 (95% CI, 0.14-0.87, P = 0.025) and 0.65 (95% CI, 0.45-0.94, P = 0.023), respectively. There was lower radiation-related pneumonitis (P = 0.015) in the SIB group because of the lower dose for the irradiated lung (irradiated-lung V5, 55.38±18.11 Gy vs. 61.95±15.45 Gy, P = 0.015). Most other OAR doses and incidences of grade ≥2 disease were similar between the two arms. Exploratory biomarker analysis reveals a trend toward superior survival benefit from SIB in patients with PD-L1 ≥1% or EGFR-mutant. CONCLUSIONS:We demonstrated that the routinely adaptive SIB strategy could significantly improve PFS and OS and reduce the dose to the irradiated lung without increasing the risk of tumor recurrence. Exploratory analyses of EGFR mutation status and PD-L1 expression suggested potential differences in treatment outcomes across biomarker-defined subgroups. This strategy represents a potentially feasible regimen to improve survival outcomes for patients with stage III LA-NSCLC eligible for definitive concurrent chemoradiotherapy and warrants further validation in larger prospective trials.
Recurrent hepatocellular carcinoma (HCC) can arise with variable molecular similarity to the primary tumor, but practical approaches for quantifying methylome divergence in paired tumors remain limited. We performed reduced representation bisulfite sequencing on paired primary and recurrent HCC lesions and matched normal margins from ten patients, quantifying clustered CpG methylation across 77,790 MspI-defined loci. Regression-based methylation shift patterns (MSPs) captured tumor-specific curve shapes, and Euclidean distances between regression-coefficient vectors grouped tumors into four MSP classes. We further introduced tH, a triangle-area metric summarizing within-patient methylome divergence between primary and recurrent tumor-associated MSPs. In this exploratory cohort, tH distinguished lower- and higher-divergence recurrence patterns that showed concordance with serum marker patterns, mutation-based tumor relatedness, and recurrence-free survival differences. Interval-based analyses revealed prominent hypermethylation at low-methylation loci, hypomethylation at high-methylation loci, and heterogeneous changes in intermediate methylation tiers. These findings establish an MSP/tH framework for quantifying methylome divergence between paired primary and recurrent HCCs and for stratifying tumors by shared epigenetic shift patterns, providing a basis for future validation in larger paired-tumor cohorts.
BACKGROUND:Transplant-associated cutaneous squamous cell carcinoma (TSCC) is one of the most common malignancies in solid organ transplant recipients and is strongly associated with long-term immunosuppression. However, the transcriptional programs and molecular mechanisms through which chronic immunosuppression reshapes intratumoral CD8⁺ T-cell differentiation remain poorly understood. METHODS:We integrated single-cell transcriptomic and T-cell receptor repertoire analyses of TSCC and immunocompetent cutaneous squamous cell carcinoma (SCC). An independent SCC cohort containing paired tumors and adjacent tissues, together with matched spatial transcriptomic data, was used to evaluate the association between EOMES and antitumor CD8⁺ T-cell differentiation. RESULTS:Single-cell transcriptomic analysis revealed marked accumulation of precursor effector-memory CD8⁺ T cells (Pre-Tem) in TSCC, accompanied by reduced cytotoxic programs and clonal expansion. Trajectory and regulatory-network analyses revealed retention of precursor-like differentiation states associated with reduced EOMES expression and regulon activity. In silico perturbation modeling predicted EOMES as a candidate transcriptional regulator linked to cytotoxic gene expression and effector differentiation. An independent SCC cohort further supported the biological relevance of EOMES-associated programs in antitumor CD8⁺ T-cell states. Cell-cell communication analysis identified CXCL10-CXCR3 signaling as a dominant pathway targeting Pre-Tem cells and related with diminished EOMES-associated differentiation programs. Spatial transcriptomics further identified spatial co-localization among CXCL10 signaling, EOMES-associated states, and Pre-Tem cells within a tumor-margin niche. CONCLUSIONS:Pre-Tem accumulation and altered differentiation states represent a previously unrecognized feature of immune dysfunction in TSCC. EOMES-associated programs were closely linked to precursor-to-effector CD8⁺ T-cell differentiation, while CXCL10-CXCR3 signaling may contribute to impaired precursor-to-effector differentiation. These findings provide a conceptual framework for understanding immune dysfunction in transplant-associated malignancies and establish a rationale for future mechanistic and translational studies.
Background: Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, yet its molecular determinants, functional dependencies, and therapeutic vulnerabilities remain incompletely characterized. Integrative analyses combining transcriptomic profiling with functional genomic datasets provide a strategy to identify essential genes, biomarkers predictive of tumor behavior and treatment response. Methods: Differential expression analysis comparing HB tumors with normal liver was processed on training cohort. These genes were integrated with DepMap CRISPR-Cas9 dependency scores to prioritize HB-essential candidates. Elastic Net regression was used to derive a 16-gene predictive signature, which was validated in an external cohort. Single-cell RNA-seq datasets were analyzed to assess expression patterns across hepatic and tumor-associated cell populations. A supervised deep-learning classifier was trained on single-cell profiles to distinguish tumor cells from hepatocytes, and SHAP values were computed to interpret gene contributions. Drug-gene interactions were queried using curated repressive compounds from DGIdb, and approved drugs were screened for relevance in pediatric cancer clinical trials. Results: A total of 789 genes were found overexpressed in HB tumors from the training transcriptome cohort. Chronos DepMap analysis identified 73 HB-essential genes that were not essential in adult liver cancer cell lines (hepatocellular carcinoma and cholangiocarcinoma). Elastic-net tuning based on the expression of 16 HBessential genes in the split training cohort enabled robust tumor-normal discrimination, with AUC = 0.88, specificity = 0.90, and sensitivity = 0.90 in internal validation. This performance was confirmed in an independent external cohort, achieving AUC = 0.99, specificity = 1.00, and sensitivity = 0.98. Single-cell validation further demonstrated tumor-specific enrichment of the signature. The deep-learning classifier (tumor cells vs. normal hepatocytes) reached high accuracy (AUC = 0.99; F1-score = 0.97), with SHAP analysis highlighting PEG10, GREB1, PLCB4, RHOBTB1, CRIM1, FSD1L, CORO2A, KIT, ANKRD50, HDAC11, ZNF233, SEMA7A, and FABP4 as major contributors. Six of these genes were confirmed to be absent or lowly expressed in the background liver microenvironment. Drug-gene interaction analysis identified HDAC11 as a potential therapeutic target of approved drugs used in pediatric oncology. Conclusions: This integrative framework combining transcriptomics, CRISPR dependency mapping, machine learning, and pharmacogenomic annotation identifies clinically relevant HB-essential genes and predictive molecular signatures for tumor identity. The derived expression-based scores provide tools for patient stratification, while drug-gene mapping highlights actionable vulnerabilities on HDAC11 with pediatric approved drugs that support rational drug repurposing strategies in hepatoblastoma.
Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are highly conserved, ubiquitously expressed scaffold proteins that play central roles in cellular physiology by forming heterodimeric ring-shaped complexes. Their subcellular localization to mitochondria, the nucleus, cytoplasm, and plasma membrane underpins a remarkable functional pleiotropy that is profoundly exploited in cancer. This review provides a comprehensive synthesis of the current understanding of PHBs in tumor biology, spanning structural features, post-translational modifications, and their integration into multiple oncogenic signaling networks. We systematically describe how PHB1 directly activates the RAS-RAF-MEK-ERK cascade through regulated phosphorylation, how both PHB1 and PHB2 fine-tune the PI3K/Akt/mTOR axis through ubiquitination-dependent scaffolding and degradation of negative regulators, and how they exert bidirectional control over Wnt/β-catenin and NF-κB pathways. A major focus is the dual role of the mitochondrial PHB complex: protecting cristae architecture and regulating the OMA1-OPA1 axis, orchestrating respiratory chain supercomplex assembly, metabolic substrate switching, and mitophagy, while simultaneously suppressing or, in specific contexts, promoting reactive oxygen species signaling and ferroptosis. The review further dissects how dynamic nucleocytoplasmic shuttling of PHBs couples metabolic status to cell cycle progression, stemness, and epigenetic remodeling through interactions with transcription factors (E2F1, p53, Sp1) and chromatin modifiers (MLL2, HDAC1). Within the tumor microenvironment, PHBs emerge as critical immunometabolic hubs that influence macrophage polarization, cGAS-STING activation, and sexual dimorphism in immune responses. We summarize the cancer-type-specific expression patterns of PHB1/2 and their prognostic value, and provide an in-depth analysis of the mechanisms by which PHBs confer resistance to platinum drugs, paclitaxel, PARP inhibitors, and radiotherapy through stabilization of anti-apoptotic proteins, mitochondrial protection, and maintenance of cancer stem cell properties. Finally, we catalogue the expanding armamentarium of PHB-targeted interventions, including small-molecule ligands, stapled peptides, DNA aptamers, and siRNA delivery platforms, and discuss the challenges and opportunities for clinical translation. By integrating molecular mechanisms with translational perspectives, this review highlights PHBs as unique regulatory nodes at the intersection of metabolism, signaling, and immunity, and advocates for precision strategies that exploit context-specific PHB functions to overcome therapy resistance and improve cancer treatment.
The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent telomere maintenance mechanism, which is frequently observed in osteosarcoma. In this study, we performed a systematic review of studies assessing ALT in patient-derived osteosarcoma samples using direct experimental assays, alongside bioinformatic analysis of large public genomic datasets to evaluate the prevalence of canonical ALT-associated alterations. Across seven eligible studies comprising 342 tumours, ALT activity was identified in 62.9% of cases. In contrast, analysis of the Target-OS and PeCan datasets demonstrated that mutations in ATRX or DAXX, and amplification of TOP3A, occur at substantially lower frequencies, collectively accounting for only a minority of tumours. Statistical comparison confirmed a significant discrepancy between experimentally-observed ALT prevalence and the frequency of these canonical ALT-associated genetic alterations. These findings indicate that canonical genomic events are insufficient to explain ALT activation in osteosarcoma and support a model of marked biological heterogeneity. Potential alternative mechanisms include nonmutational disruption of chromatin remodelling pathways, replication stress-associated processes, and epigenetic dysregulation. The data highlights the limitations of relying on sequencing-based approaches alone to infer telomere maintenance mechanisms, which could have important clinical consequences for potential ALTpathway targeting therapies. In conclusion, ALT is highly prevalent in osteosarcoma but is not adequately captured by known genetic correlates. Functional assays remain essential for accurate classification, and improved understanding of noncanonical ALT drivers will be critical for biomarker development and the design of targeted therapeutic strategies.
Purpose The vast majority of reported ALK rearrangements occur at exons 17-20. ALK-rearrangements occurring earlier in the ALK gene (eALK) are poorly characterized and rarely reported, potentially because most clinically available biomarker testing is optimized for detecting common ALK rearrangement regions. Methods Two databases, the Tempus deidentified database and Cedars-Sinai database, were retrospectively queried to characterize eALK rearrangements, as defined by rearrangements involving ALK exons 1-16. Select specimens harboring eALK rearrangements were evaluated using available FDA-approved methods (immunohistochemistry [IHC] and fluorescent in-situ hybridization [FISH]); clinical management and outcomes were evaluated for these cases. Results 39 eALK rearrangements were detected in the Tempus database and 3 were identified in the Cedars-Sinai database. Across these 42 rearrangements, there were 35 unique partner genes; rearrangements were identified in all early exons except exons 8, 10, 13 and 15, with exons 2 and 4 being most common. Prostatic, breast, leiomyosarcoma, and ovarian serous carcinoma were the most common tumor types, which may reflect database bias. In three cases, IHC and FISH were unreliable at detection (0/ 3 IHC positive, 1/3 FISH atypical positive). Limited clinical information shows partial response to ALK targeted therapies. Conclusions Novel eALK rearrangements are a distinct subclass of ALK rearrangements and were not reliably detected through FDA-approved testing modalities. Limited clinical data suggests these cancers could still respond to ALK targeted therapy.
