NTRK fusions drive the pathogenesis of a distinctive group of mesenchymal neoplasms with significant impact on classification and targeted therapy. However, unexpected NTRK fusions have been reported in other sarcoma entities, raising uncertainty over their specificity and clinical management. Herein, we investigate the incidence and structural variants of NTRK fusions among a large clinicopathologic and molecular sarcoma cohort. The goal was to distinguish primary driver NTRK fusions from potential passenger events and correlate with sarcoma histotypes. NTRK1-3 fusions were queried across a large spectrum of sarcomas, profiled by targeted DNA and/or RNAseq. Fusions were classified as oncogenic when NTRK was the 3' partner, in-frame, retained kinase domain (KD), and/or RNAseq confirmation; fusions of uncertain significance (FUS) when out-of-frame, lacking full KD, and/or RNAseq negative. We identified 48 cases with NTRK fusions, detected either by pathologist-initiated RNAseq for diagnosis (n = 27) or by clinician-initiated DNAseq for therapeutic target discovery (n = 21). For the latter subset, reflex RNAseq was activated for confirmation. Integrated review confirmed 33 (69%) oncogenic fusions. Remaining were FUS, apart from one indeterminate. In all except three cases, oncogenic fusions occurred in canonical NTRK-driven histotypes. In contrast, NTRK FUS were detected in various pathologic entities, including well-differentiated/dedifferentiated liposarcoma (n = 9, 60%), two osteosarcoma, and single cases of other subtypes. NTRK1 fusions were the most common in both oncogenic and FUS groups (61%, 67%). CDKN2A/B deletions were observed mostly in oncogenic NTRK1 fusions (71%), while MDM2/CDK4 amplifications in the NTRK1 FUS. The FUS group demonstrated lower NTRK mRNA expression, with a mean of -4.60, p < 0.001. Pan-TRK immunohistochemistry was positive in cases with oncogenic NTRK fusions, and negative in FUS cases. Only two-thirds of NTRK fusions detected were functional drivers, mostly from pathologist-driven testing of suggestive histotypes. In contrast, genomic profiling in complex sarcomas often yields passenger FUS, lacking functional impact.

There is morphological overlap between nodular necrotizing fibroblastic sarcoma (NNFS) and myxoinflammatory fibroblastic sarcoma (MIFS). Whether they represent neoplasms within the same tumor spectrum remains unclear. We performed a comparative clinicopathological, molecular, and epigenetic study of these two tumors.

With the widespread adoption of genomic testing, germline predisposition syndromes such as RUNX1-familial platelet disorder with associated myeloid malignancy (FPD-MM) are increasingly encountered in routine hematological practice. FPD-MM is driven by RUNX1 haploinsufficiency, which initially manifests as quantitative and qualitative platelet abnormalities. Over time, this constitutional defect promotes the formation of an inflammation-dominant bone marrow microenvironment, facilitating clonal hematopoiesis, clonal expansion, and the stepwise accumulation of secondary somatic alterations, ultimately leading to myeloid or lymphoid malignancies. Accurate diagnosis requires careful interpretation of tumor-based sequencing results, followed by confirmatory testing using appropriate germline specimens in conjunction with standardized variant classification frameworks. Clinical management encompasses bleeding risk mitigation and disease-specific therapy for overt hematologic neoplasms, including allogeneic hematopoietic stem cell transplantation. Genetic counseling is an essential component of donor coordination in FPD-MM, given the documented risk of donor-derived leukemia when related donors harbor the same pathogenic germline variant as the proband. Beyond the management of affected individuals, surveillance for asymptomatic variant carriers is also essential for early intervention before disease progression. This review summarizes the pathobiology, diagnostic strategy, and practical clinical management of FPD-MM, emphasizing family management as a central medical and ethical challenge at the intersection of hematology and clinical genetics.

Germline variants of DDX41 are among the most common mutations conferring hereditary predisposition to adult MDS/AML, occurring particularly frequently in MDS with increased blasts and in AML secondary to MDS. Their prevalence across disease subtypes is 3% to 9%, with approximately 60% being germline nonsense or frameshift variants that typically acquire a somatic missense second hit. The variant frequency is 2 to 3 times higher in men, and adverse co-mutations such as those in FLT3 or NRAS are uncommon. Penetrance is nearly 0% by age 40 and approximately 50% by age 90, with comparable estimates in Japanese, UK, and French population datasets. DDX41 variants account for roughly 80% of currently recognized hereditary myeloid predisposition syndromes, and DDX41-mutated MDS is challenging to stratify using IPSS-R or IPSS-M. Hypomethylating agents are effective, and the addition of venetoclax provides substantial therapeutic benefit. Notably, cases of post-transplant leukemia arising from related donors harboring DDX41 variants have been reported, highlighting the clinical importance of presymptomatic mutation screening.

The onset of hematologic malignancies is influenced not only by acquired somatic mutations but also by pathogenic germline variants to a broader extent than previously assumed. Although germline predisposition was traditionally thought to be limited to inherited bone marrow failure syndromes such as Fanconi anemia or to characteristic familial cases, pathogenic variants in RUNX1, ETV6, GATA2, and DDX41 are now known to be associated with diverse hematologic malignancies, including leukemia/MDS, across a wide age range from childhood to adulthood. With the widespread use of cancer genomic profiling tests, germline findings are encountered more frequently, which has contributed to improved diagnostic accuracy, individualized treatment selection and transplant conditioning, donor selection, and evaluation of secondary cancer risk. However, careful selection and interpretation of "normal" specimens is required given the risk of tumor cell contamination in peripheral blood. This article summarizes the overall landscape and key clinical points, and outlines prospects for multidisciplinary collaboration and evidence-building.

For an extended period, R-CHOP therapy was the standard of care for the first-line treatment of diffuse large B-cell lymphoma (DLBCL); nevertheless, approximately 30% of patients experience treatment resistance or relapse, highlighting the limitations of a "one-size-fits-all" treatment strategy. In recent years, however, the development of risk-adapted therapy based on molecular subtype identification and response-adapted therapy using circulating tumor DNA (ctDNA) to detect minimal residual disease has advanced considerably, building on Pola-R-CHP therapy, which became the new standard of care following the POLARIX trial. To further improve the cure rate of DLBCL, it is essential to integrate these molecular pathologies, the tumor microenvironment, and early treatment response assessment to establish personalized first-line treatment strategies that combine novel molecularly targeted drugs and immunotherapy.

Genomic information for hematologic malignancies is now routinely available in clinical practice, supporting the adaptation of hematopoietic cell transplantation, selection of conditioning intensity, and implementation of post-transplant maintenance therapy through refinement of disease risk assessment and minimal residual disease (MRD) measurement. This review presents the current evidence on the effective utilization of genomic information for acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). It also presents an up-to-date framework for optimal donor selection based on donor genome information, addressing both donor clonal hematopoiesis of indetermined significance and the risk that related donor candidates may carry the same hereditary predisposition. Finally, it discusses research showing that patient and donor genetic polymorphisms (SNPs) can predict transplant complications such as GVHD, and that reduced gut microbiota diversity, as detected by metagenomic analysis, impacts GVHD severity and survival. These examples illustrate the multifaceted role of genomic information in research efforts to improve hematopoietic cell transplantation outcomes.

The treatment of chronic lymphocytic leukemia (CLL) has rapidly evolved from traditional chemoimmunotherapy to molecular targeted therapies. Current recommended first-line treatment options include covalent BTK inhibitor (cBTKi: ibrutinib, acalabrutinib±obinutuzumab, and zanubrutinib)-based regimens and BCL2 inhibitor (BCL2i: venetoclax)-containing regimens (venetoclax+obinutuzumab and venetoclax+ibrutinib). The former approach relies on continuous treatment with cBTKi for long-term disease control, and the latter is a time-limited approach using BCL2i aiming for long-term treatment-free remission. Molecular and genetic features of CLL, performance status, comorbidities, social support systems, and patient preference are considered in treatment selection for CLL. The non-covalent BTK inhibitor pirtobrutinib has recently been approved for patients with relapsed or refractory CLL who have previously been treated with a cBTKi. The durability of responses to initial and subsequent treatment of CLL has greatly extended life expectancy, and newer agents including BTK degraders, next-generation BCL2 inhibitors, novel antibodies (antibodies against BAFF, CD19, or ROR1, along with CD3×CD20 bispecific antibodies), and chimeric antigen receptor T-cell therapies should further improve quality of life for all patients.

Mantle cell lymphoma (MCL) is characterized by repeated relapses and gradual disease progression under conventional cytotoxic chemotherapy. Although a variety of chemotherapy regimens have been developed to improve outcomes, direct comparisons of efficacy across regimens evaluated in different clinical trials remain challenging because of the limited number of patients in each study and the biological heterogeneity of the disease. Consequently, a universally accepted standard therapy for MCL has yet to be established. In recent years, the introduction of Bruton's tyrosine kinase (BTK) inhibitors has markedly improved the prognosis of patients with MCL. In parallel, advances in the understanding of its molecular pathogenesis have provided deeper insights into the mechanisms of drug response and resistance, as well as potential synergistic effects with other therapeutic agents. Collectively, these developments are reshaping the clinical management of MCL. With the anticipated expansion of novel therapeutic approaches, including immunotherapies, MCL has emerged as a highly active and rapidly evolving field in both clinical practice and molecular research.

Gene rearrangements of the human MLL gene (also known as KMT2A) cause leukemia with poor prognosis by generating MLL fusion oncoproteins. MLL is an epigenetic regulator that has an evolutionarily conserved role maintaining expression of homeotic (HOX) genes during embryonic development. HOX genes and other MLL target genes such as MEIS1 block differentiation and promote proliferation in hematopoietic cells. MLL gene rearrangements generate a constitutively active version of the wild-type protein, which causes overexpression of HOX genes and other target genes, leading to leukemic transformation of normal hematopoietic progenitors. MLL fusion proteins need to form a complex with endogenous menin protein to function as an oncogenic driver. Recently, small compounds that inhibit menin-MLL interaction have been developed and used in clinics in the United States. This review explains how menin inhibitors disrupt MLL fusion protein activity and discusses potential future developments.

The treatment landscape for older adults with acute myeloid leukemia (AML) has undergone a paradigm shift, transitioning from a one-size-fits-all approach to personalized medicine driven by molecular profiling and novel therapeutics. Decision-making now necessitates a comprehensive assessment of leukemia-specific factors, such as genetic mutations and cytogenetics, alongside patient-specific factors evaluated through geriatric assessment. For fit patients, the integration of CPX-351 and FLT3 inhibitors into intensive chemotherapy has significantly improved transplant eligibility and survival outcomes. Conversely, for unfit patients, combinations of venetoclax and azacitidine or IDH1 inhibitors have been established as new standards of care with high response rates. Furthermore, advances in transplant technology have demonstrated improved survival outcomes following allogeneic hematopoietic cell transplantation, even in older adults. Recent data indicate that not only intensive chemotherapy but also less intensive therapies can serve as an effective bridge to transplant, achieving favorable long-term results. Modern management of AML in older adults must respect the highly diverse values of this age group. It is essential to propose a tailored treatment approach based on a thorough evaluation of leukemia biology, physical and cognitive function, and the treatment preferences of patients and their families. Such integrated strategies are key to optimizing clinical outcomes in this heterogeneous population.

Clonal hematopoiesis (CH) refers to the age-associated expansion of hematopoietic stem cell clones carrying somatic mutations that are commonly observed in myeloid malignancies. With the widespread use of next-generation sequencing, such mutations are now frequently detected even in individuals without overt hematologic abnormalities. CH in the absence of cytopenia or hematologic malignancy is defined as clonal hematopoiesis of indeterminate potential (CHIP), whereas CH accompanied by unexplained cytopenia is classified as clonal cytopenia of undetermined significance (CCUS), a recognized pre-malignant condition with a high risk of progression to myeloid neoplasms. The molecular landscape of CH is dominated by mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1, although spliceosome genes, signaling molecules, and DNA damage-response genes are also involved. Clonal expansion and malignant transformation are shaped by selective pressures including aging, chronic inflammation, and therapy-related DNA damage. Progression risk varies widely depending on mutation type, variant allele frequency, and clonal complexity, and several predictive models have been proposed. Beyond hematologic malignancies, CH has also been linked to cardiovascular and inflammatory diseases, highlighting its broader clinical relevance and the need for risk-adapted clinical strategies.

The introduction of tyrosine kinase inhibitors (TKIs) has substantially improved outcomes for chronic-phase chronic myeloid leukemia (CML-CP). Furthermore, the development of ABL myristoyl pocket inhibitors that target specific molecular pathways has enabled adoption of treatment strategies with fewer adverse events. However, the clinical significance of somatic mutations in genes other than ABL1 in treatment resistance is attracting increasing attention. Additionally, novel TKIs and STAMP inhibitors are under development, and are expected to further improve CML management. This article summarizes the frequency and clinical impact of somatic mutations in CML-CP and reviews promising novel TKIs and STAMP inhibitors.

Lenalidomide, an immune-modulatory drug, is used to treat multiple myeloma (MM). Lenalidomide has also been investigated as a treatment for myelofibrosis (MF); however, its efficacy in this setting has not been established. We report a case of secondary MF progressing from polycythemia vera (PV) that had the poor prognostic factor del (7q) and concurrent MM, in which del (7q) disappeared and MF improved after treatment with lenalidomide. A 69-year-old woman presented to our hospital with PV in March 2022. Bone marrow examination revealed grade 2 fibrosis. The diagnosis was secondary MF progressing from PV, with JAK2 V617F and del (7q), along with IgG-κ monoclonal gammopathy of undetermined significance (MGUS). In May 2023, the appearance of new bone lesions indicated progression of MGUS to MM. Treatment with lenalidomide plus dexamethasone achieved a partial response. After this treatment, del (7q) disappeared and MF improved. The efficacy of lenalidomide in MF with del (7q) has never been reported. This case shows that lenalidomide may improve the prognosis of MF with del (7q).

An 80-year-old man was diagnosed with acute myeloid leukemia (AML), and molecular analysis identified FLT3-ITD, TKD mutations. Induction chemotherapy with daunorubicin plus cytarabine achieved hematological complete remission; however, extramedullary infiltration was detected in the skin and central nervous system. Due to this extramedullary disease, treatment with mitoxantrone plus high-dose cytarabine was administered, leading to systemic complete remission. Two cycles of the same regimen were then added. The patient relapsed 5 months later, at which time FLT3 mutations were no longer detectable by a companion diagnostic test. However, targeted sequencing analysis identified a novel FLT3-ITD positive minor clone. Treatment with venetoclax plus azacitidine was then started. The patient achieved complete remission and has remained relapse-free for more than 2 years. In this case, the FLT3 mutation companion diagnostic test result became spontaneously negative without FLT3-directed treatment, and the response to venetoclax plus azacitidine was favorable. This case highlights the importance of molecular testing not only at diagnosis but also at relapse for appropriate treatment selection.

The field of epitranscriptomics, an area of genetics concerning the regulation of gene expression via post-transcriptional RNA modification, is currently attracting substantial research attention. In epitranscriptomics, proteins, collectively termed writers, erasers, and readers, enter into complex interactions that contribute to modifying RNA, thereby maintaining biological homeostasis. However, abnormalities in the expression or function of these proteins can lead to the onset and progression of cancers and neuropsychiatric disorders. Using prostate cancer clinical specimens, I cloned a novel gene, prostate cancer antigen-1 (PCA-1), containing a domain similar to the 2-oxoglutarate, iron(II) [Fe(II)]-dependent oxygenase domain of the Escherichia coli AlkB protein and characterized by enzymatic activity associated with the demethylation of methylated RNA. This was accordingly designated AlkB homolog 3 (ALKBH3). I demonstrate that ALKBH3 is highly expressed in tumor cells in prostate, pancreatic, lung, and other cancers, and its activity is correlated with a poor prognosis. In addition, I developed novel compounds that inhibit the RNA demethylase activity of ALKBH3, thereby providing a basis for developing a first-in-class cancer therapeutic. I also succeeded in cloning the ALKBH8 gene. High ALKBH8 expression was also observed in bladder cancer cells. Furthermore, abnormalities in development and behavior were noted in the generated Alkbh8 knockout mice. On the basis of the experience gained from ALKBH3 drug discovery research, I have established a foundation system for supporting academic drug discovery research. In this review, I describe the pathway followed in integrating the findings of basic pharmaceutical and drug discovery research and further developments.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS), occurring in isolation or as part of Carney complex (CNC); its phenotypic and molecular spectra remain incompletely defined.

TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare, aggressive subtype that predominantly affects adolescents and young adults. Its marked morphologic heterogeneity can delay recognition and downstream confirmatory testing.

Despite remarkable advances in cancer drug treatment, including chemotherapy, targeted therapy, and immunotherapy, therapeutic resistance remains a formidable clinical barrier, limiting durable responses and long-term survival. Drug resistance can be broadly categorized as intrinsic, where tumors fail to respond to initial treatment, or acquired, which emerges during or after therapy due to adaptive or evolutionary processes. A comprehensive understanding of the multifactorial and dynamic nature of resistance is essential for improving treatment efficacy. In this review, we systematically examine the molecular and cellular determinants of drug response and resistance across 22 cancer types, highlighting key resistance mechanisms such as compensatory pathway activation, phenotypic plasticity, immune evasion, enhanced DNA damage repair, and the survival of drug-tolerant persister cells. These mechanisms are further contextualized across major therapeutic modalities, supported by clinical trials. We also present emerging strategies to overcome resistance, including rational drug combinations, novel agents, microbiome modulation, adaptive and intermittent therapies and advanced drug delivery systems, each illustrated with representative clinical studies. Moreover, we discuss cutting-edge tools that are revolutionizing resistance research, including single-cell and spatial multiomic profiling, patient-derived tumor organoid and xenograft (PDO/PDX) models, and artificial intelligence (AI)-powered predictive analytics. By integrating insights across molecular, cellular, and clinical dimensions, this review offers a strategic framework for understanding and tackling cancer drug resistance, with important translational implications for the future of precision oncology.

This study aimed to investigate the mechanism of total flavonoids from Smilacis Glabrae Rhizoma(SGF) against obesity-associated colorectal cancer(CRC) via regulation of fatty acid oxidation(FAO). In vivo, syngeneic subcutaneous and orthotopic xenograft models of CRC cells MC38 were established in obese mice induced by high fat diet(HFD), which was followed by the administration with SGF. The tumor volume and tumor weight were measured in the CRC subcutaneous model. The growth of CRC orthotopic tumors was monitored by a small animal in vivo imaging system. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in tumors and peritumoral adipose tissues. Immunohistochemistry, TdT-mediated dUTP nick end labeling(TUNEL), and oil red O staining were separately conducted to detect Ki67 expression, apoptosis, and lipid accumulation in tumors. Western blot was used to detect the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK) and acetyl-CoA carboxylase(ACC), as well as the expression of FAO-related proteins and cell death-related proteins in tumor tissues. In vitro, MC38 cells cultured under low-glucose and high-oleic acid conditions were taken as the research object and treated with varying concentrations of SGF for 48 h. Apoptosis rates were assessed by flow cytometry, and the expression of FAO-related and cell death-related proteins was analyzed by Western blot. Further, the prolyl hydroxylase domain-containing protein 3(PHD3) expression was subjected to RNA interference(RNAi), and the viability and apoptosis of PHD3-knockdown MC38 cells following SGF treatment were assessed by MTT assay and flow cytometry, respectively. The results showed that both high and low doses of SGF significantly inhibited tumor growth in two obese mouse xenograft models. The SGF-treated groups exhibited extensive, scattered necrotic areas within the tumor tissue, with marked destruction of tissue structure. Compared with the HFD group, the SGF-treated groups showed a significant reduction in the rate of Ki67-positive cells and a significant increase in the proportion of TUNEL-staining-positive apoptotic cells. In obese mice, subcutaneous tumors showed significantly enhanced oil red O staining, with large lipid droplets visible. The SGF-treated groups markedly reduced lipid deposition. In both models, peritumoral adipocytes were significantly enlarged after SGF treatment. The tumor tissues of obese mice exhibited significantly increased expression of FAO-related proteins cluster of differentiation 36(CD36), carnitine palmitoyltransferase 1(CPT1), and acyl-CoA dehydrogenase long chain(ACADL), as well as elevated adenosine triphosphate(ATP) content. The phosphorylation levels of upstream regulatory proteins AMPK and ACC were significantly increased, while the expression of the energy switch protein PHD3 was significantly decreased. SGF significantly reduced the protein expression of CD36, CPT1, and ACADL, decreased ATP content, inhibited AMPK and ACC phosphorylation, and increased PHD3 protein levels. This was accompanied by a significant increase in the apoptotic protein cysteine-dependent aspartate-specific protease-3(caspase-3) and significant decreases in the anti-apoptotic protein B-cell lymphoma-2(Bcl-2) and the cell cycle protein cyclin D1. In MC38 cells cultured under low-glucose and high-oleic acid conditions, SGF significantly induced apoptosis and inhibited lipid uptake. FAO-related protein expression was significantly suppressed. Caspase-3 expression was significantly increased, while Bcl-2 and cyclin D1 expression was significantly decreased. PHD3 expression was significantly elevated. In MC38 cells transfected with siPHD3, the inhibitory effect of SGF on cell viability and its pro-apoptotic effect were both significantly enhanced. In summary, SGF effectively reduces lipid transfer between adipose tissue and tumors under obese conditions, regulates the AMPK/ACC signaling pathway, and targetedly inhibits tumor FAO, thereby exerting potent antitumor effects against obesity-associated CRC.