Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy.

Acute myeloid leukemia (AML) is a heterogeneous disease with large spectrum of specific mutations and gene aberrations. Recently, the Bcl-2 inhibitor Venetoclax, in combination with hypomethylating agents (HMAs), was approved for older (> 65 years) AML patients, as well as for those unfit for intensive induction chemotherapy. In addition to Bcl-2 inhibition, Venetoclax also induces generation of reactive oxygen species (ROS). We demonstrated that distinct fraction exhibiting specific features arises during 24 h of sample exposure to Venetoclax. This fraction displays characteristic preapoptotic markers as mitochondria depolarization and partial Annexin V surface positivity. Moreover, monitoring of ROS showed negative correlation between signals detected using H2DCFDA and CellROX probes pointing to dynamic ROS changes induced by Venetoclax. The addition of HMA (Decitabine) had almost no effect on cell viability or ROS production but caused proliferation arrest in sensitive cells. In our panel of AML cell lines and primary AML samples we have found a correlation between ROS production, markers of apoptosis, and attenuation of Bcl-2 activity after Venetoclax treatment. Level of Mcl-1, another antiapoptotic protein from the Bcl-2 family, was reduced in sensitive cells, but increased in the resistant samples in response to Venetoclax. Moreover, the nucleolar protein nucleolin (NCL), which is frequently overexpressed in AML cells, was significantly deregulated in Venetoclax-treated cells. In particular, both NCL protein level and specific phosphorylation decreased in fractions sensitive to Venetoclax. Our findings suggest that Venetoclax targets distinct cell subpopulation, and that ability of a cell to follow increased ROS drives its response to Venetoclax.

Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.

Immune-cold melanomas respond poorly to immune checkpoint blockade (ICB). We assessed whether RNA-seq-based immune subtyping and connectivity mapping could nominate repurposable compounds to shift immune-depleted melanoma toward an immune-enriched phenotype. Using RNA-seq from 432 The Cancer Genome Atlas Skin Cutaneous Melanoma cases, we assigned published molecular functional portrait subtypes and compared depleted (D, n = 169) with combined immune-enriched (IE + IE/F, n = 184) subtypes using limma-voom. The resulting 300-up/300-down signature underwent Library of Integrated Network-based Cellular Signatures L1000 connectivity mapping, with compound-level aggregation and mechanism-of-action annotation. The pipeline was rerun on two stratified split-half folds. Canonical cytotoxic and antigen-presentation genes (CD8A, PDCD1, CXCL9, CXCL10, CD3D, GZMB, PRF1) were depleted in D, validating the contrast. Raw connectivity-mapping hits were dominated by generic cytotoxic-stress compounds. After aggregation and filtering, DNA methyltransferase (DNMT) inhibitors showed the most consistent positive pattern; fdcyd, azacitidine, and RG-108, but not decitabine, were robust to sample-type sensitivity analysis. Class enrichment was not significant after correction [false discovery rate (FDR) q = 0.126]. Indoleamine 2,3-dioxygenase inhibitors trended negative (FDR q = 0.095), and mitogen-activated protein kinase kinase inhibitors showed no class-level pattern (FDR q = 0.698). Across both folds, all seven canonical genes replicated and all four DNMT inhibitors retained above-median ranks, but the cold-elevated signature module was markedly less stable than the hot-elevated module (25.7 vs. 88.7% overlap). This suggestive pattern converges with a phase II trial of azacitidine/carboplatin priming before anti-programmed death-ligand 1 rechallenge in ICB-resistant melanoma, supporting prospective evaluation.

Background and Clinical Relevance: The association between acute myeloid leukemia (AML) and monoclonal gammopathy of undetermined significance (MGUS) is rare and likely coincidental, due to the similar epidemiology of these two blood disorders in older AML patients who are not eligible for intensive chemotherapy or aggressive treatment, as they can be excessively myelosuppressive. Such treatments include those containing venetoclax, an easy-to-use all-oral form of decitabine-cedazuridine (DEC-C), which is now available and approved for AML in addition to standard parenteral DNA methyltransferase inhibitors, which have been commonly used in routine clinical practice for about two decades in patients unsuitable for intensive chemotherapy (IC). Case Presentation: A 71-year-old woman developed a therapy-related acute myeloid leukemia (t-AML) seven years after the discovery of the plasma cell dyscrasia. She had carried an asymptomatic and non-progressing IgG-λ MGUS since 2019 while affected by breast cancer, which was cured with chemotherapy and radiotherapy. BM smear and trephine biopsy at the time of t-AML diagnosis showed 30% myelomonoblasts and 8% plasma cells, while SPEP showed the presence of 15 g/L of monoclonal protein. However, considering her age and other medical and personal history, the patient was found unsuitable for IC as well as venetoclax treatment because of the myelosuppressive effect of the therapy. Therefore, she received DEC-C oral monotherapy. After four DEC-C cycles, she achieved CR with hematological incomplete recovery (CRi). During DEC-C monotherapy, serum immunofixation (IF) and BM evaluations after 12 months of treatment showed gradual clearance of the IgG-λ paraprotein and BM plasma cells. Maintenance therapy with oral DEC-C is ongoing for 18 months after achieving CRi, without any signs of toxicity or infection. Conclusions: This report describes the first anecdotal case of t-AML responding to DEC-C with concomitant clearance of the paraprotein associated with MGUS.

Acute myeloid leukemia (AML) primarily affects older adults, many of whom are unsuitable for intensive chemotherapy. Hypomethylating agents (HMA) -intravenous (IV) decitabine and subcutaneous (SC) azacitidine- are standard therapeutic options but require frequent hospital visits and substantial healthcare resource use. Oral decitabine/cedazuridine (DEC-C) offers a therapeutically equivalent alternative that may reduce hospital resource burden and improve patient convenience. This study estimated and compared the economic and organizational impact of IV, SC, and oral HMA administration in AML patients unfit for standard intensive chemotherapy, from the perspective of the Spanish National Health System. A micro‑costing model quantified direct non‑pharmacological costs associated solely with the administration route across five domains: drug preparation and administration, treatment‑related hospitalizations, medical transportation, catheter management, and infections. Resource use was derived from a survey of 30 healthcare professionals across 16 hospitals and valued using official tariffs. Costs were calculated separately for induction and subsequent cycles; drug acquisition costs were excluded. Non‑pharmacological costs per patient were €9,998 for IV decitabine, €12,177 for SC azacitidine, and €1,306 for oral DEC‑C, representing cost reductions of 87% and 89% for oral therapy versus IV and SC, respectively. Savings were driven mainly by reductions in hospitalization (58-61%), transport (13-22%), infections (9%-12%), administration‑related activities (11-12%) and the avoidance of catheter-related costs. Oral therapy also markedly reduced resource utilization, including 40-50 fewer hours of healthcare professional time, 8-9 fewer inpatient days, and 4-8 fewer ambulance transfers per patient. Catheter use decreased by 33%, and infection risk declined by 87% versus IV and 54% versus SC. Oral administration substantially reduces direct non‑drug costs and frees hospital capacity, offering meaningful organizational efficiencies and contributing to the sustainability of AML care within a resource‑constrained health system. These findings reinforce the value of integrating oral HMAs into clinical pathways.

Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Post-transplant treatment may provide a third anti-leukemic effect after conditioning-related cytotoxicity has waned and before graft-versus-leukemia immunity is fully established. Prophylactic maintenance is initiated in high-risk patients despite undetectable measurable residual disease (MRD), whereas pre-emptive treatment is triggered by the detection of MRD or declining donor chimerism. Hypomethylating agents (HMAs) are biologically attractive and feasible with post-transplant-adapted dosing, but prophylactic azacitidine did not improve relapse-free or overall survival in a randomized trial. Newer decitabine-based, oral HMA, and venetoclax-containing strategies require confirmation. FMS-like tyrosine kinase 3 (FLT3) inhibitors have the strongest prospective evidence in a molecularly selected population. The QuANTUM-First trial supports quizartinib throughout induction, consolidation, and continuation, including after transplantation, whereas the MORPHO trial directly evaluated post-transplant gilteritinib and identified its clearest benefit in patients with detectable peri-transplant FLT3-internal tandem duplication (FLT3-ITD) MRD. This review traces the evolution of relapse prevention strategies and proposes a practical framework integrating baseline risk, serial MRD assessment, targetable biology, immune intervention, and post-transplant feasibility.

The addition of venetoclax to hypomethylating agents (HMAs) is standard for older adults with newly diagnosed acute myeloid leukemia (AML). However, prolonged venetoclax (VEN) exposure can cause cytopenias and infections, raising questions about optimal duration. We conducted a single‑center retrospective study of 102 patients treated between 2018 and 2025 with azacitidine or decitabine plus VEN administered for 14 (n = 22), 21 (n = 48), or 28 (n = 32) days per 28‑day cycle. Baseline cytogenetic and molecular profiling, responses by 2022/2024 ELN criteria, measurable residual disease (MRD), cumulative incidence of relapse (CIR), disease‑free survival (DFS), and overall survival (OS) were analyzed using competing‑risks regression and Cox models. Median age was 68 years and patients received a median of 4 cycles. Composite remission (CR/CRi/CRh/MLFS) was 66.7%, with MRD negativity in 75.0% of responders. Remission and MRD negativity rates did not differ significantly across VEN‑duration cohorts. Median OS and DFS were 17.3 and 12.3 months, respectively, with no significant differences in OS, DFS, and CIR between 14‑, 21‑, and 28‑day cohorts. Grade ≥ 3 cytopenias and transfusion independence rates also did not differ significantly. In this cohort, shortening VEN exposure to 14 or 21 days did not show a significant difference in response, survival, relapse risk, and toxicity profiles relative to a 28‑day schedule in our cohort. These findings support further prospective evaluation of reduced VEN durations in this population.

Myelodysplastic syndromes (MDS) are clonal disorders with high risk of progression to acute myeloid leukemia (AML). Allogeneic haematopoietic stem cell transplantation (allo-HSCT), including haploidentical HSCT (haplo-HSCT), is the only curative option. Age-stratified selection of conditioning regimens based on organ reserve and comorbidity burdens has been routine clinical practice for many years. However, recent developments warrant a critical re-examination: the incorporation of hypomethylating agents and targeted therapies (decitabine, venetoclax), the introduction of the quantitative Transplant Conditioning Intensity (TCI) score, and emerging data in patients aged ≥ 70 years. This review summarizes age-stratified regimens: myeloablative (MAC), reduced-intensity (RIC), and reduced-toxicity (RTC). In younger patients (< 50 years), MAC achieves 3-year overall survival (OS) > 70% and non-relapse mortality (NRM) < 15%. In middle-aged (50-60 years) and elderly (> 60 years) patients, RIC/RTC yield OS of 60%-70% with NRM < 20%, though these estimates derive largely from retrospective or single-center studies. Adding targeted/hypomethylating agents (e.g., decitabine, venetoclax) has shown promise in reducing relapse in high-risk patients. Age-stratified conditioning combined with these agents forms the core of individualized transplant strategies, reducing NRM and improving efficacy. Prospective, MDS-specific randomized trials are urgently needed to transform these preliminary observations into evidence-based standards.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Acute myeloid leukemia (AML) with concurrent multiple fusion genes is extremely rare and characterized by high malignancy, poor chemotherapy response, and dismal prognosis. Here we report a 32-year-old male patient diagnosed with de novo high-risk AML harboring BCOR mutations, AML1-MDS1/EVI1, AML1-EAP, and BCR-ABL1 p210 fusion genes. The patient received induction chemotherapy with IA+VEN (idarubicin, cytarabine and venetoclax) regimen and achieved complete remission (CR); however, disease progression occurred during the first consolidation therapy. Subsequently, salvage chemotherapy combined with dasatinib was administered, and the patient reattained complete remission with incomplete hematologic recovery (CRi). The patient then underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his HLA-mismatched father. Post-transplant maintenance therapy consisting of chidamide, decitabine, and dasatinib was administered regularly. At the latest follow-up 3 months after transplantation, the patient remained in continuous molecular remission, with negative minimal residual disease (MRD) and significantly reduced BCR::ABL1 and EVI1 transcript levels. This case indicates that individualized sequential therapy including targeted agents, combination chemotherapy, allo-HSCT with chidamide-containing conditioning, and post-transplant epigenetic maintenance may provide effective disease control and favorable long-term outcomes for ultra-high-risk AML with multiple adverse molecular abnormalities.

Despite considerable advances in cancer therapy, the intrinsic heterogeneity of malignant cells continues to compromise therapeutic efficacy with conventional monotherapies, driving the need for combination treatments to achieve more durable and complete responses. The limited efficacy of conventional chemotherapy is largely attributable to the immunosuppressive tumor microenvironment, which is frequently perpetuated by epigenetic mechanisms, including aberrant DNA methylation. To overcome these limitations, we hypothesized that Decitabine (Dac)-mediated sensitization could dramatically enhance Sorafenib (Sor)-induced ferroptosis, and to test this synergy, we developed an innovative biomimetic codelivery platform comprising polymer micelles loaded with Sor surface-coated with exosomes encapsulating Dac (Exo&PM/D + S). This platform facilitates codelivery, enabling Dac-mediated DNA hypomethylation to remodel the tumor microenvironment and promote Sor-triggered ferroptosis. In vitro, Exo&PM/D + S exhibited potent anti-tumor activity by concurrently enhancing DNA demethylation and ROS accumulation. In mouse neuroblastoma models, the system significantly suppressed tumor growth, stimulated antitumor immunity, and extended survival. Mechanistic studies confirmed that Dac potentiates Sor-induced ferroptosis through epigenetic modulation. Thus, Exo&PM/D + S represents a promising nanotherapeutic strategy that synergizes epigenetic modulation with ferroptosis induction for enhanced anti-tumor efficacy.

Sickle cell disease remains a major cause of childhood morbidity and mortality, particularly in sub-Saharan Africa. In September, 2025, WHO convened the Paediatric Drug Optimization for Sickle Cell Disease process to review approved therapies, pipeline candidates, and potentially curative approaches, and define priorities for children and adolescents. Hydroxyurea (hydroxycarbamide) was confirmed as the leading near-term priority, with age-appropriate soluble or dispersible formulations identified as essential to improve equitable paediatric access; preferred and minimum characteristics were defined through a formal target product profile. Among investigational agents, pyruvate kinase activators and decitabine plus tetrahydrouridine (NDec) emerged as promising candidates for paediatric investigation on the basis of emerging efficacy data and programmatic potential. Intersecting research priorities included identifying appropriate clinical trial endpoints, strengthening early and inclusive paediatric investigation, and proactively ensuring that the promise of potential cure through gene therapy does not delay investment in scalable disease-modifying treatments.