To improve the tolerability of posttransplant maintenance and outcomes despite poor-risk disease genetics, we conducted a phase 1 study of venetoclax (Ven) with FluBu2 (fludarabine/busulfan) reduced-intensity chemotherapy transplantation using tacrolimus/methotrexate graft-versus-host disease (GVHD) prophylaxis, followed by all-oral Ven/decitabine-cedazuridine (Ven/Dec-c) maintenance in patients with poor-risk MDS/AML (myelodysplastic syndrome/acute myeloid leukemia; N = 30). Overall, 58% had previous Ven exposure and 63% had TP53 mutation; 15/19 had TP53 multihit state. At a median of +55 days, prophylactic maintenance therapy with Ven (400 mg on days 1-14) and Dec-c (35 mg decitabine and 100 mg cedazuridine tablet on days 1, 3, and 5, or days 1, 2, and 3) was initiated for 8 cycles of 42 days each in 26 of 30 patients (87%; of the remaining patients, 3 relapsed early and 1 withdrew). On maintenance, grade 3/4 neutropenia (96%) occurred although infections were rare (n = 2). No dose-limiting toxicities occurred. The 6-month acute GVHD grade 2 to 4 rate was 13%. The 1-year moderate/severe chronic GVHD rate was 31%. At a median follow-up of 25.1 months (range, 15-33), median overall survival (OS) and progression-free survival (PFS) were not reached. On maintenance, 2-year OS was 77%, PFS was 62%, nonrelapse mortality was 0%, and cumulative incidence of relapse was 38%. Exploratory studies identified 96% of patients had pretransplant next-generation sequencing molecular residual disease (MRD) positivity, favorable survival in those with non-TP53 MRD positivity, and delayed conversion on maintenance in 11 of 18 (61%) with TP53-MRD positivity. Patient-reported outcomes assessed in the first 6 months of maintenance were stable except for emotional function, which significantly improved. This trial was registered at www.ClinicalTrials.gov as NCT03613532.

Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study.

In parallel with the evolution of epidemiological evidence over nearly two decades, various advisory and regulatory groups in Europe and the United States have conducted several hazard assessments on inhalation exposure to formaldehyde and risk of leukemia. All of the hazard assessments addressed all or the myeloid leukemias (MLs) combined, and none focused on the acute type, etiologically distinct and shown to have a chemical cause (e.g., benzene). However, conclusions regarding formaldehyde as a human leukemogen have been conflicting, although largely based on the same modest body of evidence. As there are no known animal models for formaldehyde and leukemia (any type), good evidence that formaldehyde cannot reach the bone marrow, and no demonstrated mechanism whereby formaldehyde induces leukemia, the hazard assessment ultimately rests on about ten epidemiological studies and their interpretation. Beginning in 2009 with the International Agency for Research on Cancer (IARC), followed by other groups in the United States and Europe, formaldehyde has been classified as causing human ML. On the other hand, the EU Scientific Committee on Occupational Exposure Limits (SCOEL) and the European Chemicals Agency (ECHA) concluded that formaldehyde unlikely causes ML. Multiple classifications of formaldehyde as leukemogenic were motivated by claims of "new studies," including Beane Freeman etal., Hauptmann etal., and Zhang etal. Closer evaluation of these reveals no increased occurrence of ML in Beane Freeman etal. and several important criticisms in the others that limit their value for classifying formaldehyde. Nevertheless, the hazard assessments summarized here varied with some observing consistent positive findings and some others-including recent meta-analyses-finding no association. That similar hazard assessment approaches applied to the same modest collection of epidemiological studies can lead to different-and even conflicting-causal conclusions is problematic. One might reasonably conclude that the research methods for evaluating epidemiological data are unreliable, leading to non-replicable and sometimes unexplained findings and conclusions. Assuming that frameworks for critical review and synthesis of epidemiological evidence are reasonably valid-and faithfully followed-it remains possible that they are methodologically inadequate, inadvertently increasing the potential for subjective elements to be incorporated and allowed to influence interpretations and conclusions. A serious international effort to develop robust and replicable hazard assessment methods based on epidemiological evidence and promote universal adoption is overdue.

The cytosine analog 5-aza-2'-deoxycytidine (decitabine; DAC) covalently inhibits DNA methyltransferase 1 (DNMT1), the maintenance DNA methyltransferase, and induces SUMOylation of DNA-trapped DNMT1, promoting proteasomal degradation. However, how DNMT1 SUMOylation is regulated and its biological impact remains unclear. Here, using interphase Xenopus egg extracts that reconstitute maintenance DNA methylation in vitro, we identify death domain-associated protein (DAXX) as a regulator of SUMOylation on chromatin-retained, inactive DNMT1. First, adding 5-aza-dCTP, the triphosphate form of decitabine, induced DNMT1 accumulation on chromatin and robust SUMO2/3 conjugation. Chromatin mass spectrometry (CHROMASS) revealed DAXX enrichment on 5-aza-dCTP-treated chromatin in a SUMO-dependent manner, and DAXX depletion suppressed 5-aza-dCTP induced DNMT1 SUMOylation. Furthermore, GSK-3484862, a non-covalent DNMT1 inhibitor, drove DNMT1 accumulation on chromatin and triggered DAXX-dependent DNMT1 SUMOylation. We also demonstrated that DAXX loss increased decitabine sensitivity in the myeloid leukemia (AML) cell line THP-1. Together, these findings show that DAXX promotes SUMOylation of DNMT1 trapped on DNA under both covalent and non-covalent trapping conditions.

Background/aimChronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome (Ph), which occurs as a result of t(9;22). In 5%–10% of CML cases, variant t(9;22)s are observed. Additionally, while t(9;22) is formed, deletions can be observed in chromosomes 9 and 22. These deletions are observed more frequently in variant t(9;22). There is conflicting information in the literature about the prognostic effects of variant t(9;22) and deletions of 9q and 22q. There is also limited information about the frequency and breakpoints of other chromosomes involved in the variant t(9;22). Signal patterns other than the classical signal pattern of FISH analysis indicate deletions and variant translocations. In this study, we aimed to investigate the clinical significance of nonclassical FISH signal patterns and to determine the frequency of variant translocations.Materials and methodsBone marrow samples from 231 newly diagnosed CML patients were analyzed by conventional cytogenetics and FISH.ResultsAs a result of FISH analysis, nonclassical FISH signal patterns were detected in 49/231 cases, and variant t(9;22) was detected in seven cases by conventional cytogenetics. It was determined that chromosomes 1, 3, 5, 7, 8, and 21 were involved in variant t(9;22). When cases with classical and nonclassical signal patterns were compared in terms of 6th- and 12th-month treatment responses, survival times, and treatment changes, it was found that cases with classical signal patterns had significantly higher treatment responses at the 6th month (p < 0.001).ConclusionBecause variant translocations are extremely rare and involve many different chromosomal breaks, a large number of cases are needed to clearly understand their prognostic implications. Due to the limitations of conventional cytogenetic analyses, it should be considered in patient follow-up that nonclassical FISH signal patterns indicating deletions and/or variant translocations may cause a delay in obtaining a complete cytogenetic response at the 6th month.

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25+ leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB-mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry-based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase-driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

A novel GMP-manufactured medicinal product candidate composed of NK and γδ T cells as adjunct immunotherapy for hematopoietic stem cell transplantation.

circPCMTD1: A protein-coding circular RNA that regulates DNA damage response in BCR/ABL1-positive leukemias.

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML), the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here, we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality, and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase POLRMT and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.

Metabolic syndrome (MetS) is a common complication in survivors of childhood acute lymphoblastic and myeloid leukemia (AL), and a major risk factor for premature cardiovascular disease, type-2-diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Lifestyle interventions, including a healthy diet and physical activity, are the cornerstone of the management of MetS. In long-term childhood AL survivors with MetS, the benefits of classical lifestyle interventions remain poorly documented. We conducted a one-year dietary and behavioral intervention with monthly dietitian coaching in this specific population. We assessed clinical, biological metabolic parameters, noninvasive biomarkers of hepatic steatosis and fibrosis, and eating habits at baseline and after one year of coaching. We enrolled 48 patients from the LEA cohort, diagnosed with MetS. The mean age was 32 years. At baseline, 62.2% of patients had hepatic steatosis and 15% had fibrosis F3-F4 (VCTE > 8kPa). Daily energy intakes were already limited (average, 1611Kcal/day). After one year of lifestyle coaching, the body mass index (27.1vs. 26.5kg/m2, p = 0.041) and the waist circumference (91.9vs. 89.5cm, p = 0.027) had decreased. Daily intakes had significantly decreased (1213Kcal/day) with a healthier diet. Hepatic and metabolic parameters had not significantly improved in the study population. Liver steatosis was improved only in the subgroup of patients who lost weight and/or waist circumference. Survivors of childhood AL have a high prevalence of MASLD at a young age. Classical lifestyle intervention appears incompletely efficient in improving metabolic and hepatic parameters in this specific population. New therapeutic approaches to reduce MetS and its complications in this unique population need to be studied.

BAF complexes are ATP-dependent chromatin remodelers that govern gene expression and cellular identity. The non-canonical BAF (ncBAF) complex, with BRD9 as its signature component, orchestrates chromatin remodeling essential for balanced hematopoiesis. BRD9 loss disrupts enhancer-promoter interactions and CTCF-mediated chromatin architecture, causing myeloid skewing, impaired lymphoid differentiation, and diminished hematopoietic stem cell (HSC) fitness-phenotypes recapitulating physiological aging. This mechanism underlies aging-related pathologies such as myelodysplastic syndromes (MDS), in which spliceosomal mutations in SF3B1 trigger aberrant BRD9 splicing and destabilize its mRNA. Remarkably, BRD9 exhibits context-dependent functions: its depletion consistently promotes differentiation and apoptosis in myeloid leukemias, contrasting its differential roles in myeloid differentiation in adult versus fetal hematopoiesis. Thus, BRD9 mechanistically links spliceosomal dysfunction to chromatin dysregulation, bridging aging-associated disease and malignant transformation through context-dependent roles. Among the diverse assemblies of BAF family, these findings position the BRD9-ncBAF axis as both a critical determinant of hematopoietic fate decisions and a promising therapeutic target in hematologic malignancies.

Modulation of IL-10 and CD96 in Myeloid Leukemia: Implications for Chemoresistance and Immunotherapy Strategies

The epidemiology and clinical characteristics of familial myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) remain poorly understood, particularly among Native Hawaiians and other Pacific Islanders (NHOPI). To investigate the real-world evidence in this area, we conducted a retrospective study at the Queen's Medical Center, Hawaii's largest tertiary referral hospital. This study is based solely on self-reported family histories and interviews, without germline genetic validation. Among 1686 MDS/AML patients who presented between January 2012 and July 2023, 12 (0.71%) had familial MDS/AML and 25 (1.48%) had a family history of unspecified leukemia. While no NHOPI were identified among patients with familial MDS/AML, 20% of patients with a family history of unspecified leukemia were NHOPI. The median age at diagnosis of familial MDS/AML was 70years, and 50% of familial MDS patients had MDS with low blasts based on the WHO 2022 classification. The median overall survival (OS) time and 5-year OS rate for familial MDS were 12.7years and 75.0%, respectively. In contrast, familial AML had a median OS time of 0.85years and a 3-year OS rate of 33.3%. Our study provides new insights into familial MDS/AML in Hawaii's multiethnic population.

The American Society for Apheresis recommends leukapheresis as a category II recommendation for symptomatic hyperleukocytosis. Mortality in these patients varies between 8%-29%. However, no tool is currently available to assess the mortality risk following the procedure. This study aims to assess the factors associated with in-hospital mortality and develop a risk stratification tool consisting of clinically relevant variables to categorize patients based on their mortality risk following the procedure. The National Inpatient Sample Database (2016-2021) and ICD-10 coding were utilized to identify adults with leukemia who underwent leukapheresis. Multivariate logistic regression models were constructed to identify independent factors of mortality. A scoring system was constructed to identify the risks of mortality using the variables in the model and their associated odds ratio (OR). The cumulative risk score was divided into three strata: low (mortality < 20%), intermediate (20%-50%), and high risk (> 50%). Of the estimated 3555 patients who underwent leukapheresis, 40.1% also received chemotherapy. Most patients who underwent leukapheresis had myeloid leukemia (52.2%), followed by lymphoid leukemia (14.2%), monocytic leukemia (6.2%), and the remaining were other types of leukemia. Variables incorporated into the scoring system include: monocytic leukemia, age over 50, morbid obesity, and interventions performed before leukapheresis, such as mechanical ventilation and blood transfusions. The cumulative mortality score ranged from 0 to 30, categorizing patients into high risk (score > 13), intermediate risk (6-13), and low risk (0-5). The risk score demonstrated a performance with an area under the curve of 0.82. A novel simplified scoring tool to predict in-hospital mortality in leukemia patients requiring leukapheresis is presented here. This tool can assist in preprocedural risk assessment, help guide management planning, and consideration of other treatment modalities.

HSPC-like blasts in acute lymphoblastic leukemia: biology and therapeutic opportunities.

BackgroundLeukemia presents a significant and evolving public health challenge in Saudi Arabia, yet long-term nationwide epidemiological trends are unavailable. This study aimed to characterize temporal, demographic, and regional patterns in leukemia incidence from 1997 to 2022.MethodsWe conducted a retrospective nationwide analysis using the Saudi Cancer Registry and Global Burden of Disease data. We calculated age-standardized incidence rates (ASR), age-specific incidence rates (AIR) per 100 000, and average/annual percentage changes (AAPC/APC) by age, sex, leukemia type, and administrative region.ResultsThe overall ASR was 5.9, with an increase over time (AAPC = 2.28, 95% CI 1.68‒2.87), sharply accelerating after 2016 (APC = 9.47, 95% CI 6.21‒15.18). This trend was driven by a dual burden in pediatric (0–14 years; boys AAPC = 2.67, 95% CI 1.95‒3.40; girls AAPC = 2.38, 95% CI 1.41‒3.66), and 50+ adults (males AAPC = 1.7, 95% CI 0.55‒2.86; females AAPC = 3.0, 95% CI 1.76‒4.25), including a 147% AIR increase among males aged 75+. Myeloid leukemia (AAPC = 2.68, 95% CI 0.67‒3.66) became the most common type after 2019, overtaking lymphoid leukemia. Regionally, Riyadh had the highest overall burden (ASR = 6.7), while the Northern region exhibited the fastest growth (AAPC = 10.51, 95% CI 4.09‒16.89). Qassim was the sole exception (AAPC = − 4.54, 95% CI -6.43‒-2.63).ConclusionLeukemia incidence in Saudi Arabia is accelerating at a rate exceeding global trends, highlighting the need for targeted, regionally adapted surveillance. Further research into underlying demographic and regional drivers is essential to guide effective cancer control planning.Supplementary InformationThe online version contains supplementary material available at 10.1007/s44197-025-00470-2.

Rising mortality attributed to agranulocytosis in myeloid leukemia among older adults in the United States : A time trend analysis

A novel protocol of dual passing cord blood pre-/post-transplant reduced relapse in TCRαβ cell depleted HCT

Targeting immunoproteasome-dependent β-catenin degradation as a therapeutic strategy in Relapsed/Refractory acute lymphoblastic leukemia

Epidemiological survey of familial myelodysplastic syndromes/acute myeloid leukemia in Hawaii