Search Results (324)

Advances in the molecular characterization of acute myeloid leukemia (AML) in recent decades have driven the development and clinical introduction of several targeted therapies, and menin inhibitors are the most recent additions to the therapeutic arsenal of AML treatments. The KMT2A and NPM1 loci have been the focus of intense investigation over the past two decades because of their well-established roles leukemogenesis, particularly in pre-clinical models of AML involving human xenografts. The ability of KMT2A and NPM1 aberrancies to drive and sustain leukemogenesis has provided a strong rationale for the development of therapeutic strategies to disrupt these molecular pathways. Menin inhibitors preferentially eliminate clones harboring KMT2A rearrangements or NPM1 mutations due to the dependence of these leukemia cells on the menin–KMT2A complex and its downstream HOXA9/MEIS signaling to sustain leukemic self-renewal and disease maintenance. In this review, we discuss the biological rationale for menin–MLL disruption in patients with acute leukemia with KMT2A rearrangement or NPM1 mutation. We explore data from the landmark AUGMENT-101 and KOMET-001 trials, which have led to regulatory approval of revumenib and ziftomenib for select patients. We also explore cutting-edge studies using menin inhibitors in combination strategies, including data from KOMET-007. The evidence supporting combination approaches remains based on early-phase, single-arm trials with relatively short follow-up, and longer-term and comparative data are needed to define their clinical benefit. We highlight resistance mechanisms that have emerged from the use of contemporary menin inhibitors and efforts aimed at addressing this resistance, with a focus on emerging clinical data on enzomenib and bleximenib. Finally, we discuss prospects on the putative role of menin inhibitors in the measurable residual disease (MRD)-positive and maintenance settings in AML. Menin inhibitors have successfully transitioned from biological proof-of-concept to approved targeted therapy, and future advances will depend on rational front line combination strategies, MRD-guided treatment, post-transplant maintenance strategies, and therapeutic sequencing informed by mechanisms of resistance. Full article

Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. Methods: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug–gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. Results: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C>T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C>T and T>C transitions, indicating endogenous mutational processes. Analysis of drug–gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. Conclusions: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis. Full article

Ketogenic metabolic therapy (KMT), typically implemented as a ketogenic diet (KD), has re-emerged as a potential adjuvant strategy in oncology. Its rationale is grounded in the metabolic reprogramming of cancer cells, including their reliance on glucose and lipid substrates and the signaling functions of ketone bodies. Despite extensive preclinical evidence of anti-proliferative and immunomodulatory effects, clinical translation in cancer therapy has been slow and inconsistent. This review critically examines the mechanistic basis, experimental and clinical evidence, and translational challenges of KMT across epithelial cancers. We emphasize that “ketogenic interventions” comprise mechanistically distinct modalities, including classical KD, fasting, fasting-mimicking diets, and exogenous ketone supplementation, which are frequently conflated yet differ substantially in their endocrine and metabolic contexts. Across clinical studies, KMT is generally feasible and associated with improvements in quality of life and metabolic parameters; however, robust evidence for the survival benefit of KMT remains limited and heterogeneous. Mechanistically, ketone bodies exert both metabolic and signaling functions, including inhibition of histone deacetylases, lysine β-hydroxybutyrylation, and receptor-mediated effects. Tumor responses are highly context-dependent: ketolytic capacity, governed by enzymes such as OXCT1, can render ketones either a metabolic vulnerability or an alternative fuel for cancer cells. KMT can modify the complex tumor microenvironment, exerting potentially opposing effects on cancer cells, immune cell populations, fibroblasts, and adipocytes. We argue that the central limitation of the field is not a lack of biological activity, but of insufficient integration of tumor-intrinsic metabolism, host physiology, and microenvironmental context. KD/KMT should therefore be regarded not as a universal anticancer therapy, but as a stratified metabolic intervention, whose progress will depend on biomarker-guided patient selection, improved experimental models, and rational combination strategies within a “press-pulse” therapeutic framework. Full article

Acute myeloid leukemia (AML) harboring KMT2A rearrangements (KMT2A-r) accounts for approximately 5–10% of newly diagnosed cases and represents a high-risk AML subtype associated with poor clinical outcomes despite intensive treatment strategies, including allogeneic hematopoietic stem cell transplantation (HSCT). KMT2A-r AML is also characterized by a higher incidence of extramedullary disease compared with other AML subtypes. Therapeutic options for patients with relapsed/refractory (R/R) disease, particularly after post-HSCT relapse, remain extremely limited. In recent years, menin inhibitors have emerged as a promising targeted therapeutic class for KMT2A-r and NPM1-mutated AML by disrupting the aberrant HOX/MEIS1 transcriptional program. Revumenib, a first-in-class menin inhibitor, has shown encouraging efficacy in early-phase clinical trials. Other menin inhibitors, including ziftomenib, bleximenib, and enzomenib, have also demonstrated clinical activity, with distinct pharmacokinetic, pharmacodynamic, and safety profiles. We report the case of a 36-year-old patient with KMT2A-r AML who relapsed after HSCT with both bone marrow and hepatic involvement. Compassionate-use treatment with revumenib (160 mg twice daily on days 1–28 of each 28-day cycle) induced, after two treatment cycles, complete hematologic remission with no detectable abnormal myeloid blast population by multiparameter flow cytometry (MFC) and complete radiological resolution of hepatic lesions. However, despite prior intrathecal CNS-directed therapy and sustained systemic disease control, the patient subsequently developed an isolated central nervous system (CNS) relapse. This case highlights a potential discordance between systemic and CNS disease control during menin inhibitor therapy and emphasizes the need for further investigation into CNS surveillance and disease management in patients achieving deep systemic responses. Full article

The amplification of KMT2A, a gene involved in hematopoietic stem cell function, is extremely rare in acute leukemias, especially in mixed-phenotype acute leukemia. We present the case of a 62-year-old patient diagnosed with acute myeloid leukemia, myelodysplasia-related (AML-MR) with immunophenotypic features suggestive of B/myeloid mixed-phenotype acute leukemia (MPAL), with the presence of multiple KMT2A gene amplifications and a very aggressive and complicated clinical course ending in failure despite intensive treatment. KMT2A amplification in MPAL could be a risk factor suggesting adverse outcomes. Full article

KMT2A-rearranged (MLL-r) leukemias are highly aggressive hematological malignancies that require improved targeted therapies. DOT1L (histone H3K79 methyltransferase) functions as a critical oncogenic driver and represents an important therapeutic target in these high-risk leukemias. However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) have been modest, attributed to suboptimal pharmacokinetics and, more fundamentally, to the recognition that DOT1L possesses methyltransferase-independent functions that evade catalytic inhibition. This highlights the need for strategies that abrogate the full spectrum of DOT1L activity to effectively treat these high-risk leukemias. Proteolysis-targeting chimeras (PROTACs), which induce selective degradation of the DOT1L protein rather than inhibiting its catalytic activity, have therefore emerged as a promising approach. Notably, VHL-recruiting DOT1L PROTACs, such as DOT1L808, have demonstrated improved pharmacokinetic profiles and potent antileukemic activity in preclinical in vivo models. However, these findings remain preclinical, and significant challenges including oral bioavailability, potential toxicity, and lack of clinical validation must be addressed before clinical translation. In this review, we provide an overview of the evolving understanding of the biology of DOT1L, discuss existing MLL small molecule therapies, and evaluate current advances in therapeutically targeting DOT1L, with particular focus on the targeted degradation of DOT1L as a promising therapeutic strategy for high-risk KMT2A-r leukemia. Full article

Background/Objectives: Identifying molecular liabilities and understanding disease heterogeneity are prerequisites for advancing therapies in T-cell prolymphocytic leukemia (T-PLL), a rare T-cell malignancy with a poor prognosis. Methods: RNA-seq profiling of T-PLL samples (n = 10) and the normal counterpart (n = 5) allowed us to report gene expression and pathway alterations in malignant cells, revealing that non-coding, antisense and circular RNA expression is profoundly altered in T-PLL. Results: T-PLL displayed activation of several oncogenic pathways, particularly PI3K/AKT/mTOR and Wnt, suppression of healthy T-cell activities and cell death escape. Tumor suppressor lncRNAs (NEAT1, MIAT and LUCAT1) with reduced expression and upregulated oncogenic pro-proliferative lncRNAs (FIRRE, TERC, XIST and PVT1) were identified. CircRNAs ectopically expressed in T-PLL included circSEMA4B and circSATB1, linked to the Wnt pathway, circFIRRE and oncogenic circPVT1 and circFKBP5. Focusing on five genes with validated recurrent oncogenic variants (STAT5B, JAK3, ATM, KMT2C, and ARID1A), we investigated genotype/phenotype relations. A multiple predictor linear model suggested potential links between driver variants and alterations in gene and circRNA expression, including association between STAT5B mutations and LTF upregulation, JAK3 lesions and increased PLXNA4 expression along with CCR4 suppression. Conclusions: Our transcriptomic profiling and genotype–phenotype association analysis identified specific genes, non-coding RNAs, pathways and candidate genotype-associated transcriptional signatures that warrant further investigation as potential targets for the development of new therapeutic approaches for this rare and heterogeneous malignancy. Full article

Background: Upper tract urothelial carcinoma (UTUC) is a rare malignancy representing approximately 5–10% of all urothelial cancers. Key risk factors include smoking, chemical exposures, selected metabolic conditions, and hereditary cancer syndromes. This narrative review summarises current knowledge on UTUC molecular pathogenesis, major risk determinants, and contemporary therapeutic strategies. Methods: This study was conducted as a narrative review with a structured literature search. PubMed, Web of Science, Embase, and Scopus were searched using predefined combinations of UTUC-related terms covering molecular pathogenesis, carcinogenic risk factors, and treatment strategies. The review was prepared according to SANRA principles to improve transparency and consistency; however, no formal systematic review methodology or meta-analysis was performed. Results: Available genomic studies indicate that UTUC has a molecular profile distinct from urothelial bladder carcinoma (UBC), with recurrent alterations involving FGFR3, HRAS, KMT2D, CDKN2A, KRAS, MYC, and BRIP1. Smoking, aristolochic acid exposure, Lynch syndrome, and possibly early-onset urolithiasis contribute to carcinogenesis through distinct but incompletely understood mechanisms. Surgical treatment remains the standard of care for high-risk localised disease, whereas perioperative chemotherapy, immunotherapy, and targeted agents are expanding treatment options, particularly in advanced disease. A substantial proportion of the therapeutic evidence, however, is derived from broader urothelial carcinoma populations rather than UTUC-specific studies. Conclusions: UTUC is biologically heterogeneous and shaped by both molecular alterations and environmental exposures. Although substantial progress has been made, important gaps remain in understanding UTUC-specific carcinogenic mechanisms and in defining evidence-based personalised treatment strategies. Better integration of molecular, environmental, and clinical data is needed to improve risk stratification and treatment selection. Full article

Histone-modifying enzymes and histone post-translational modifications (PTMs) play key roles in the organization (euchromatin versus heterochromatin) and function (active versus silenced genes) of chromatin. The abundance and activity of these enzymes, along with their associated histone PTMs, are often altered in cancer cells, leading to deregulated gene expression. The expression of the KMT2A-MLLT3 protein, resulting from a chromosomal translocation in mixed-lineage leukemia (MLL), a subtype of acute myeloid leukemia, augments transcription elongation, promoting the expression of HOXA9 and MEIS1, genes that play critical roles in MLL development. Bortezomib, a proteasome inhibitor, has been effective at treating various cancers. In this study, we compared the impact of bortezomib on histone PTMs in the MLL cell line MOLM-13 and the chronic myeloid leukemic (CML) cell line K562. We report that MOLM-13 had a greater level of histone H2B monoubiquitinated at lysine 120 (H2BK120ub) and histone H3 dimethylated at lysine 79 (H3K79me2) (modifications involved in elongation) and similar levels of histone H2A monoubiquitinated at lysine 119 (H2AK119ub). Bortezomib treatment resulted in significant reductions in H2BK120ub and H2AK119ub levels, as well as in transcript levels of genes involved in MLL development. Full article

Background: Sarcomatoid carcinoma of the upper urinary tract (SCUT) is a rare and aggressive malignancy. Due to its rarity, the molecular landscape and the prevalence of potentially targetable alterations are poorly characterized. We aimed to compare the clinical, pathological, and genomic profiles of SCUT and upper tract urothelial carcinoma (UTUC). Methods: We leveraged the Tempus Lens clinically annotated genomic dataset to extract clinicopathologic and somatic genomic alteration data from patients with UTUC and SCUT. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Wilcoxon rank-sum test for continuous variables and the Chi-square test/Fisher’s exact test for categorical variables. Mutational frequencies and pairwise comparisons were performed to assess significant differences between groups. Results: In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had SCUT. Patients with SCUT were younger at diagnosis, 61 years (interquartile range (IQR) 54, 70), compared to UTUC, 71 years (IQR 64, 77) (p < 0.001), and were more likely to have node-positive disease at presentation (all p < 0.001). SCUT patients were more likely to show visceral metastases to the lung (44% vs. 21%), bone (31% vs. 17%), and brain (7% vs. 1%), compared to UTUC (all p < 0.05). Among SCUT patients, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among UTUC patients, the most common were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). Compared to UTUC, SCUT was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p < 0.05). SCUT was depleted in FGFR3 (0% vs. 25%) and FGF4 (0% vs. 8%) mutations compared to UTUC (both p < 0.05). Targetable alterations were observed in SCUT, including NF2, SETD2, and PTEN. Conclusion: Compared with UTUC, SCUT exhibits a more aggressive clinical and genomic phenotype, characterized by enrichment in NF2, SETD2, PBRM1, and PTEN. These findings underscore the divergent molecular landscape of SCUT and highlight potentially targetable genomic alterations. Full article

(1) Background: KMT2A (alias MLL) is located at chromosome 11q23 and encodes histone methyltransferase 2A which activates target genes via chromatin methylation of histone H3 lysine K4. Mutations of KMT2A, including partial tandem duplication (PTD) and fusion with partner genes, are present in both lymphoid and myeloid acute leukemia. More than 100 various KMT2A fusion genes have been described, with only a minority represented by cell line models. (2) Methods: Cytogenetic and genomic copy number analyses, PCR, Western blot and RNA-sequencing were performed to characterize aberrations in acute myeloid leukemia (AML) cell line KOPM-88. Bioinformatic analysis of public AML patient data revealed differentially expressed genes. Functional analyses were performed by siRNA-mediated knockdown and live-cell imaging. (3) Results: The AML cell line KOPM-88 is derived from a boy at relapse and has been reported to carry t(X;11)(q24;q23), albeit with uncharacterized breakpoints. In KOPM-88 we identified fusion gene KMT2A::SEPTIN6 generated by this translocation, but excluded KMT2A-PTD. KMT2A::SEPTIN6 activated bone morphogenetic protein (BMP)-signalling and inhibited expression of HOXA7 and HOXA9. BMP signalling in turn activated cell proliferation and inhibited CDKN2B expression. (4) Conclusions: KOPM-88 contains fusion gene KMT2A::SEPTIN6, representing the only cell line model for this rare type of KMT2A rearrangement. KOPM-88 may serve to advance novel therapeutic treatments for KMT2A::SEPTIN6-positive AML. Full article

Progression-free survival (PFS) is an important clinical endpoint in Luminal A breast cancer (BC), yet the molecular determinants of recurrence remain incompletely understood. This study aimed to identify recurrence-associated transcriptomic alterations across age-defined patient subgroups and evaluate their predictive utility using machine learning (ML). Gene expression profiles and clinical data from the METABRIC cohort were analyzed in premenopausal, postmenopausal non-geriatric, and geriatric patients with Luminal A BC. Differential expression analysis identified 32 significantly dysregulated genes, of which 15 genes with |log₂FC| ≥ 2 were selected for detailed characterization. Among these, KMT2D, RFNG, IGF1, and CDKN2C exhibited consistent recurrence-associated expression patterns across patient subgroups, whereas ATM, RPTOR, and RICTOR displayed subgroup-dependent expression profiles. Feature selection analysis identified KMT2D as the most influential molecular predictor, while age, NPI, and tumor size were the most important clinical variables. The integrated clinicopathological–transcriptomic XGBoost model achieved the best predictive performance (AUC = 0.71; accuracy = 0.78) and outperformed baseline models based only on clinicopathological variables. Sensitivity analysis and independent external validation supported the robustness of the principal candidate biomarkers. These findings provide preliminary evidence supporting the investigation of transcriptomic biomarkers in combination with clinical variables for recurrence classification in Luminal A BC. However, further validation in independent cohorts is needed before their potential utility can be fully assessed. Full article

The prognostic significance of next-generation sequencing (NGS) findings during the hormone-sensitive phase of prostate cancer remains incompletely characterized. This retrospective cohort study included 92 patients who underwent NGS analysis on tumor tissue between 2019 and 2025. The primary endpoint was time to castration-resistant prostate cancer (CRPC) from androgen deprivation therapy (ADT) initiation; secondary endpoints were overall survival from ADT initiation (OS-ADT) and from diagnosis. Kaplan-Meier and Cox regression analyses were performed. CRPC developed in 66 patients (71.7%) at a median of 21.1 months. The most frequently altered genes were ATR (35.9%), PTEN (28.3%), TP53 (26.1%), and BRCA2 (15.2%). KMT2C alteration (5.4%) was the strongest independent genomic predictor of shorter time to CRPC (HR = 6.804, p = 0.003) and OS-ADT (HR = 4.730, p = 0.019). TP53 alteration independently predicted shorter OS-ADT (HR = 1.810, p = 0.038). High genomic burden independently predicted shorter time to CRPC (HR = 1.917, p = 0.032). Homologous recombination repair deficiency was not associated with outcomes, attributable to high ATR alteration frequency introducing pathway heterogeneity. Mismatch repair deficiency showed a borderline association with shorter OS-ADT (20.7 vs. 44.0 months; p = 0.060). An exploratory composite risk score stratified patients into three prognostic groups with markedly different outcomes (HR = 7.904, p = 0.001). NGS analysis during the hormone-sensitive phase identifies independent predictors of castration resistance, supporting its integration at ADT initiation for risk stratification and biomarker-guided treatment planning. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes. Full article

Lung cancer remains the leading cause of cancer-related death, and, despite significant advancements in targeted therapy and immunotherapy, survival for patients with advanced non-small cell lung cancer (NSCLC) remains poor. An emerging area of interest is the role of epigenetic modifiers in both the pathogenesis and treatment of NSCLC. Herein, we review a selected group of chromatin-modifying genes implicated in NSCLC, organized by their function as writers (KMT2A, SETD2, and EZH2), erasers (the KDM2, KDM5, and KDM6 demethylase families), and readers (the SWI/SNF subunits SMARCA4 and ARID1A). Writers deposit activating or repressive marks on histones to regulate gene transcription, erasers remove these marks, and readers reposition nucleosomes and control DNA accessibility. Dysregulation of these genes has been associated with tumor proliferation, metastasis, treatment resistance, and altered response to immune checkpoint blockade in NSCLC. Research within this topic is emerging, and these genes represent promising potential therapeutic avenues as well as potential biomarkers. Finally, we review the clinical trials involving targeting these genes available in the current literature. The number of NSCLC-specific trials remains limited, with the most active development in SMARCA2 inhibitors for SMARCA4-mutated tumors and EZH2 inhibitors given in tandem with PD-1 blockade. We hope this review is hypothesis-generating for ongoing investigation into the role of epigenetic modifiers in NSCLC and their potential to expand the therapeutic armamentarium available for this disease. Full article