Bi-directional association between RUNX1::RUNX1T1 and KIT mutations in acute myeloid leukemia: A multicenter genomic profiling study.

Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.

The mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm represents a clonal proliferation of plasmacytoid dendritic cells within myeloproliferative and myelodysplastic disorders. This entity was recently recognized as a distinct condition in the fifth edition of the World Health Organization classification of hematolymphoid tumors. It occurs in approximately 4.9% of acute myeloid leukemia cases. The pathogenic mechanisms underlying this proliferation and the role of these cells in disease progression remain poorly understood. Nevertheless, the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia is related to distinct genetic abnormalities, worse prognosis, reduced overall survival, lower sensitivity to conventional acute myeloid leukemia therapies, and an increased risk of relapse. It also displays distinct immunophenotypic features compared to other types of mature plasmacytoid dendritic cell proliferation, raising questions about its classification and diagnostic criteria. This review provides a comprehensive overview of current knowledge regarding the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia, including terminology inconsistencies; the role of plasmacytoid dendritic cells in this entity; associated genetic alterations; immunophenotypic and morphological characteristics of blasts and plasmacytoid dendritic cells; clinical outcomes and prognostic impact; and therapeutic approaches and perspectives. Synthesizing current evidence may help improve disease recognition and highlight gaps in knowledge to guide future research.

CLL1 polymeric nanoparticles loaded with PI3K/BRD4 dual inhibitor MDP5 and azacitidine as a novel treatment for TP53 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) is caused by uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Historically, research has emphasized the role of protein-coding genes in the development of AML. However, with the human genome project revealing that 98% of the transcriptome consists of non-protein-coding RNAs, recent studies have explored how the large classes of noncoding RNAs (ncRNAs) contribute to AML. Although there are many types of ncRNAs, much attention has been placed on understanding the function of long ncRNAs (lncRNAs) and small ncRNAs known as microRNAs (miRNAs). lncRNAs are >200 nucleotides, whereas mature miRNAs are typically 18 to 25 nucleotides. lncRNAs are involved in miRNA and protein sequestration and act as transcriptional and translational regulators, whereas miRNAs facilitate mRNA degradation and translational inhibition. In addition to lncRNAs and miRNAs, two additional types of ncRNAs, namely small nucleolar RNAs (snoRNAs) and circular RNAs (circRNAs), have recently garnered attention for their roles in AML. Here, we discuss how these four distinct classes of ncRNAs may aid in disease diagnosis and prognosis as well as the mechanisms by which their dysregulation contributes to AML.

Correlation of NPM1 immunohistochemistry with mutation subtypes, clinicopathologic variables and molecular testing in AML with NPM1 mutation.

Machine learning and deep learning tools have been proposed to improve survival prediction in acute myeloid leukemia (AML), but comparative benchmarks remain unclear. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 searches of PubMed, Scopus, and Web of Science (January 2018 to March 2025) identified studies developing or externally validating artificial intelligence (AI)-based models for overall or relapse-free survival reporting area under the receiver operating characteristic (ROC) area under the curve (AUC). Two reviewers extracted design, population, features, algorithms, and training/validation AUCs and assessed risk of bias using Prediction model Risk of Bias Assessment Tool (PROBAST). Random-effects meta-analysis (DerSimonian-Laird) pooled validation AUCs overall and by horizon (1/2/3/5 years) and feature category (gene-centric vs nongenetic). Optimism bias was the training-validation AUC difference. We included 24 predominantly retrospective studies (137 model cohorts; ∼51 055 patients). Of 120 PROBAST domain ratings, 74% were low risk, 25% unclear, and <1% high; statistical analysis was the weakest domain. Across 73 independent validation cohorts, the pooled AUC was 0.769 (95% confidence interval [CI], 0.742-0.795) with substantial between-study variability (I 2 = 95.7%; meaning most of the spread reflects real differences across cohorts rather than chance). Validation AUCs increased with longer horizons (1-year, 0.748; 2-year, 0.760; 3-year, 0.760; 5-year, 0.833). Pooled development AUC was 0.801 vs 0.749 in matched validation sets (ΔAUC, 0.052; 95% CI, 0.041-0.063). Nongenetic models achieved a pooled validation AUC of 0.776 vs 0.741 for gene-centric models (ΔAUC, 0.035; P = .085). AML AI prognostic models show moderate discrimination with modest optimism but substantial heterogeneity and limited prospective validation, supporting standardized reporting and rigorous external evaluation.

Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.

Older adults represent the majority of patients with acute myeloid leukemia (AML), and an increasing proportion receive allogeneic hematopoietic cell transplantation (alloHCT). Mutations in the FMS-like tyrosine kinase 3 gene (FLT3) confer high relapse risk, and post-transplant maintenance with FLT3 tyrosine kinase inhibitors (FLT3-TKIs) is guideline-recommended. However, real-world utilization, adherence, and tolerability of FLT3-TKIs in older adults remain poorly characterized. Using 100% Medicare claims (Parts A/B/D and Medicare Advantage encounter data), we conducted a retrospective cohort study of beneficiaries ≥65years old with AML who received alloHCT between January 1, 2016 and June 30, 2024, and initiated FLT3-TKI maintenance (gilteritinib, midostaurin, or sorafenib) within 100days post-transplant. Baseline demographics, comorbidities, prior therapy, and health care resource utilization (HCRU) were captured from 2010 through the index date. Adherence was assessed using proportion of days covered (PDC). Dose modification, FLT3-TKI switching, and post-transplant HCRU were evaluated descriptively. Centers for Medicare & Medicaid Services suppression rules were applied throughout. Of 7403 eligible older adults with AML undergoing alloHCT, 150 (2.0%) initiated FLT3-TKI maintenance (gilteritinib: 54.7%, midostaurin: 24.0%, sorafenib: 21.3%). Mean age was 70.5years, and 59.3% had Charlson Comorbidity Index ≥4. Utilization of post-transplant FLT3-TKIs was sustained from 2020 onwards at approximately 20% of eligible patients annually. Overall adherence was modest, with a mean PDC of 47% and very few patients achieving PDC ≥80%. Higher mean PDC was observed in patients ≥70years of age, those with fewer comorbidities, those previously treated with low-intensity chemotherapy, and those who received gilteritinib as maintenance. Among patients treated with gilteritinib, two-thirds had no evidence of dose change, and no patients switched to an alternative FLT3-TKI. Across all patients, post-alloHCT HCRU was predominantly outpatient visits, with low hospitalization rates across FLT3-TKIs. In this first real-world analysis of post-alloHCT FLT3-TKI maintenance in older adults, utilization was low and adherence was modest, although not impaired by age alone. Gilteritinib demonstrated the highest adherence and appeared to have favorable tolerability. Strategies to improve adherence and prospective data in older adults are needed to maximize the benefits of FLT3-TKI maintenance in this population.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are haematological malignancies characterized by the uncontrolled proliferation of immature, dysplastic myeloid stem and progenitor cells. These diseases exist on a biological continuum, with many MDS patients eventually progressing to AML. Both conditions predominantly affect older adults, who are often ineligible for intensive chemotherapy and stem cell transplantation due to comorbidities and frailty. For such patients, hypomethylating agents (HMAs) represent a critical therapeutic option, offering lower-intensity treatment that can induce temporary remission and extend survival. However, HMA responses are transient, with inevitable resistance leading to fatal relapse. Despite the clinical significance of HMA resistance, the underlying mechanisms remain poorly understood, and effective treatment strategies for HMA-relapsed disease are lacking. This review provides a comprehensive update on the current clinical use of HMA-based therapies in AML and MDS, and highlights the significant challenge of relapse. We then summarise available data on the molecular features of acquired HMA resistance, revealing complex and inter-connected drivers of disease recurrence.

Heme synthesis inhibition induces the intrinsic apoptosis pathway in leukemia with OSGIN1 upregulation.

A real-world analysis of the impact of azole antifungal prophylaxis on outcomes in patients with newly diagnosed acute myeloid leukemia treated with venetoclax-based therapy.

Rosettes in Acute Myeloid Leukemia: a Rare Misleading Cytology.

Fusion genes are major drivers of acute leukemia. Conventional diagnostics are limited in detecting the diverse fusions included in recently updated acute leukemia classifications. We evaluated the fusion detection performance of RNA sequencing (RNA-seq) compared with that of conventional diagnostics in patients with acute leukemia. We retrospectively obtained the data of 101 patients with acute leukemia who underwent conventional diagnostics (i.e., karyotyping, FISH, or multiplex reverse transcription PCR) at diagnosis at Samsung Medical Center, Seoul, Korea, between September 2022 and September 2023. Whole RNA-seq was performed using the Illumina Stranded mRNA Prep kit (Illumina, San Diego, CA, USA). The concordance, sensitivity, and specificity of RNA-seq for fusion gene detection were compared with those of conventional diagnostics. RNA-seq helped identify 52 fusion genes in 51 (50.5%) of 101 patients, with detection rates of 40.7%, 70.3%, 37.5%, and 50% in acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia, respectively. RNA-seq showed 83.3% sensitivity and 80.8% concordance with conventional diagnostics; it missed eight fusions, likely because of low transcript abundance or enhancer hijacking. RNA-seq also helped clarify three previously unspecified rearrangements and detected 12 fusions (21.4%) in 56 cases that tested negative with conventional diagnostics, including four novel (KMT2A::THAP12, RUNX1::PRPF19, MLLT10::UBE2L6, and FUS::ZNF362) and three rare (HNRNPH1::ERG, RUNX1::USP42, and ETV6::NCOA2) fusions. This was the first study to evaluate the performance of whole RNA-seq in fusion detection in patients with acute leukemia in Korea. Incorporating RNA-seq into diagnostic workflows may facilitate earlier and more precise therapeutic decisions and improve prognostic assessment in patients with acute leukemia.

Mutant NPM1-regulated estrogen signaling promotes leukemia cell survival by upregulating HGF and represents a therapeutic vulnerability.

Sustained MYC overexpression drives myeloid differentiation block and acquisition of leukemic phenotypes.

Loss of cystathionine-β-synthase contributes to elevated OXPHOS, a vulnerability in Ara-C-resistant Myeloid Leukemia in Down syndrome.

Optimization of the fragment binding to hinge region for a potent PIM kinase inhibitor based on N-pyridinyl amide scaffold.

Background: Iliopsoas abscess (IPA) is a rare but potentially life-threatening condition characterized by purulent infection within the psoas compartment. Immunocompromised patients, particularly those with malignancy, are at increased risk due to factors such as neutropenia, mucosal barrier injury, and prior instrumentation. While both hematogenous and contiguous sources of infection are described, there is limited literature characterizing IPA specifically in cancer patients. Methods: We conducted a focused literature review of IPA in oncologic populations and present a case series of 3 patients with active or recently diagnosed malignancy who developed psoas abscesses. Each case was examined for clinical presentation, diagnostic findings, microbiologic profile, and management strategies. Results: The first patient, with metastatic colon cancer and a chronic enterocutaneous fistula, developed a polymicrobial left psoas abscess including Escherichia coli , Veillonella , and Streptococcus anginosus . The second patient, with therapy-related acute myeloid leukemia (AML), presented with profound neutropenia and a monomicrobial MRSA abscess. The third patient, with newly diagnosed multiple myeloma, had a small left-sided psoas abscess in the context of MRSA bacteremia, spinal discitis, and paraspinal extension. All patients underwent CT-guided drainage and received targeted antimicrobial therapy based on culture data. Discussion: This series highlights the heterogeneity of IPA in cancer patients, including varied routes of infection (fistula formation and hematogenous spread), microbial profiles (polymicrobial vs. MRSA), and radiographic findings. The diagnostic challenge is compounded by nonspecific symptoms and frequent absence of the classic psoas triad, especially in neutropenic individuals. Imaging remains central to diagnosis, and management requires individualized antimicrobial therapy and source control. As cancer survival improves and immunosuppressive therapies expand, clinicians should maintain a high index of suspicion for IPA in oncologic patients with abdominal or hip pain, even in the absence of systemic signs.

Discovery of a potent thienodiazepine derivative as a novel BRD4 degrader.