Acute myeloid leukemia (AML) is a heterogeneous and devastating hematologic malignancy characterized by differentiation blockage and immature progenitor accumulation, positioning differentiation therapy as a promising therapeutic strategy. However, clinical success is largely confined to acute promyelocytic leukemia (APL) and isocitrate dehydrogenase (IDH)-mutated AML, leaving most AML subtypes with unmet needs. Herein, novel noscapine derivative ES428 is discovered that induces AML differentiation and exhibits potent anti-AML efficacy across diverse AML cell lines, primary patient samples, as well as cell line- and patient-derived xenograft models. Target deconvolution with combinatorial strategies identifies dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine synthesis, as the direct functional target. Integration of molecular dynamics simulations and comprehensive structure-activity relationship studies elucidates ES428's unique mechanism via simultaneous engagement with DHODH and mitochondrial membrane lipids. This dual-engagement underpins ES428's enhanced target engagement, efficacy, and selectivity in physiologically relevant mitochondrial membrane environment, potentially through stabilizing ES428-DHODH interaction in situ and facilitating ES428's selective mitochondrial localization. Furthermore, ES428 triggers a mechanistic cascade linking decreased pyrimidine synthesis, reduced O-linked N-acetylglycosylation (O-GlcNAcylation), EP300/CREBBP catalytic inhibition, and transcriptional reprogramming. Our findings identify promising lead candidates, establish a novel DHODH-targeting strategy, and provide important mechanistic insights to advance differentiation therapies for myeloid malignancies.

We conducted a multiomics analysis of paediatric acute promyelocytic leukaemia (APL) in 36 patients enrolled in the Japanese AML-P05 study. Targeted deep sequencing identified EP300 mutations (n = 2) and MYC-internal tandem duplication (ITD) (n = 1), which have not been previously reported in APLs. DNA methylation analysis classified 34 paediatric APLs into two groups: hypermethylation and hypomethylation. Patients in the hypermethylation group had significantly worse outcomes compared to those in the hypomethylation group (3-year overall survival: 80% vs. 100%, p = 0.043; 3-year event-free survival: 73% vs. 95%, p = 0.049). Remarkably, the EBF1-binding motif was enriched in 82.3% of the CpG sites that were differentially methylated between the hyper- and hypomethylation groups, and these sites were predominantly located in enhancer regions. Among the 1427 genes that were significantly differentially expressed between the two groups, EP300 was significantly downregulated in the hypermethylation group. Pathway analyses revealed global transcriptional downregulation in the hypermethylation group; however, MYC, a known EP300-repressed gene, was upregulated within the G2M checkpoint. Our findings suggest a potential link among enhancer-based epigenetic dysregulation involving DNA methylation at EBF1-binding sites, EP300 dysfunction and MYC activation. These alterations may contribute to disease heterogeneity and prognosis in paediatric APL.

A 49-year-old man developed therapy-related acute myeloid leukemia (t-AML) nine years after undergoing treatment for acute promyelocytic leukemia. A genetic analysis revealed a TP53 mutation and a complex karyotype featuring der(5;17)(p10;q10) translocation. This combination is associated with an extremely poor prognosis and chemoresistance. However, the patient achieved complete remission with CPX-351 (liposomal daunorubicin/cytarabine) and subsequently underwent allogeneic hematopoietic stem cell transplantation. He has remained in remission for over five months after the transplant. CPX-351 followed by early transplantation may be an important therapeutic option for selected high-risk patients, such as those with TP53-mutatied t-AML.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by the PML-RARA fusion gene and a high risk of coagulopathy. Type 2 diabetes mellitus (T2DM) is increasingly diagnosed in children and adolescents. To our knowledge, the concomitant diagnosis of these two conditions in the pediatric population has not been previously reported. We report the case of a 10-year-old girl presenting with fatigue, abdominal pain, and fever. Laboratory investigations revealed severe thrombocytopenia, leukocytosis, and 63% circulating blasts on peripheral blood smear. Bone marrow aspiration, immunophenotyping, and molecular analysis confirmed APL through detection of the t(15;17)(q24.1;q21.2) translocation and PML-RARA fusion gene. Based on a white blood cell count of 16.9 × 10[9]/L and a platelet count of 10 × 10[9]/L, the patient was classified as high-risk APL according to the Sanz classification. Severe disseminated intravascular coagulation was present at diagnosis. Concurrent metabolic evaluation demonstrated marked hyperglycemia, elevated HbA1c (8.1%), hyperinsulinemia, atherogenic dyslipidemia, and negative pancreatic autoantibodies, supporting a concomitant diagnosis of T2DM in the setting of overweight status, acanthosis nigricans, and a positive family history. Treatment was initiated according to the AML-MA 2011 induction protocol, comprising cytarabine and daunorubicin combined with all-trans retinoic acid (ATRA), intensive transfusion support, and a basal-bolus insulin regimen. At 18 months of follow-up, the patient remained in complete hematological remission under joint hematological and endocrinological surveillance. This case highlights the importance of considering metabolic disorders in children with hematologic malignancies who present with risk factors for insulin resistance. Emerging evidence suggests potential biological links between metabolic dysregulation and hematological malignancies. Early multidisciplinary management enabled successful control of both conditions and a favorable clinical outcome.

Cancer development arises from dynamic interactions between inherited susceptibility and modifiable environmental exposures, among which diet plays a central role. Carotenoids, lipophilic plant-derived pigments including lycopene, α-carotene, and β-carotene, and retinoids, the vitamin A derivatives that regulate gene transcription via retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been extensively investigated for their chemopreventive and therapeutic potential. This review aims to provide an integrated, mechanism-based synthesis of the roles of lycopene, α- and β-carotene, and retinoids in cancer chemoprevention and to clarify the conditions under which they are most likely to be effective. Beyond summarizing established antioxidant and nuclear-receptor mechanisms, we highlight as a novel emphasis the epigenetic actions of these compounds, including effects on DNA methylation, histone modification, and microRNA regulation, and we integrate these with the well-recognized divergence between dietary and high-dose supplement outcomes. Experimental evidence demonstrates that carotenoids modulate oxidative stress, inflammation, proliferation, apoptosis, angiogenesis, and metastasis through pathways such as Nrf2/ARE, NF-κB, STAT3, Akt/mTOR, MAPK, and Wnt/β-catenin. Lycopene, in particular, exhibits strong antioxidant capacity and multi-target signaling effects, while provitamin A carotenoids additionally influence retinoid-mediated transcriptional programs. Retinoids exert broader differentiation-inducing and antiproliferative effects through direct nuclear receptor signaling and represent one of the few successful differentiation therapies in oncology, most notably in acute promyelocytic leukemia. Epidemiologic studies generally associate higher dietary carotenoid intake with reduced risk of several malignancies, including prostate, breast, lung, colorectal, and gastric cancers. However, randomized trials of isolated high-dose supplementation, particularly β-carotene in smokers, have demonstrated null or harmful effects, highlighting a critical divergence between whole-food dietary patterns and pharmacologic supplementation. In conclusion, carotenoids and retinoids possess biologically plausible anticancer properties, yet their clinical utility remains context dependent. Future research should prioritize biomarker-guided, precision-based strategies, standardized formulations, and whole-food dietary approaches to clarify their role in cancer prevention and treatment.

A 47-year-old man presented with leukocytosis and absolute lymphocytosis. Peripheral blood smear examination revealed atypical lymphoid cells containing striking Auer rod-like cytoplasmic inclusions, creating a strong morphologic impression of acute promyelocytic leukemia. However, flow cytometry demonstrated a mature monoclonal B cell population lacking myeloid differentiation, and bone marrow biopsy established the diagnosis of marginal zone lymphoma. This rare case highlights a major diagnostic pitfall and underscores that Auer rod-like inclusions are not exclusively restricted to myeloid neoplasms.

Background: This review aims to provide a comprehensive and practical overview of the evolving role of autologous transplantation in leukaemias, a strategy that was once largely abandoned but has recently regained interest in selected clinical settings. Methods: We reviewed the historical development of autologous transplantation in acute leukaemias, including the early period during which autologous transplantation was considered inferior to allogeneic approaches because of limited graft purification techniques and the inability to induce effective graft-versus-leukaemia (GVL)-like immune responses. We further summarise more recent experimental strategies aimed at improving stem cell purification and enhancing anti-leukaemic immune activity in autologous settings. In addition, we discuss how advances in measurable residual disease (MRD) assessment and molecular risk stratification have contributed to the renewed interest in autologous transplantation in selected subgroups of leukaemia patients. Results: This review identifies clinical situations in which autologous transplantation remains an important therapeutic option, including plasma cell leukaemia, where it continues to represent a standard first-line approach. We also discuss well-defined patient subgroups, particularly selected AML subtypes with intermediate-risk molecular profiles and acute promyelocytic leukaemia (APL) in second remission, in which outcomes following autologous transplantation may be comparable to, or occasionally superior to, those achieved with allogeneic transplantation. In contrast, autologous transplantation currently plays only a limited role in diseases such as chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Although attempts to induce potent anti-leukaemic immune effects in autologous settings have so far shown limited clinical efficacy, several emerging strategies appear promising and may further expand the role of autologous transplantation, particularly in elderly or frail patients. Discussion: Overall, current molecular and MRD-based risk stratification strategies, together with emerging immunological and graft-manipulation approaches, may redefine the role of autologous transplantation as a personalised therapeutic option in selected subgroups of leukaemia patients.