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

Ecotropic viral integration site 1 (EVI1) is essential for hematopoietic stem cell maintenance, and its aberrant expression is a significant adverse prognostic indicator in myeloid leukemia. EVI1 overexpression typically occurs due to chromosomal rearrangement involving 3q26. However, aberrant EVI1 expression is still observed in numerous cases without 3q26 abnormalities, leading to similarly poor outcomes, while the mechanism behind EVI1 overexpression in these cases remains largely unknown. Here, we performed genome-wide CRISPR screening using cells with GFP knock-in at the EVI1 locus and identified zinc finger protein 91 (ZFP91) was the leading activator of EVI1. ZFP91 knockout significantly reduced EVI1 expression and cell proliferation. We also showed that ZFP91 binds to the EVI1 promoter, enhancing H3K4me3/H3K27ac and chromatin accessibility. Our data showed that the ZFP91-EVI1 axis plays a critical role for activation of EVI1 in myeloid leukemia. Our screening approach represents a powerful and unbiased method for identifying expression regulators that can be broadly applied across a range of contexts.

Introduction. Hyperleukocytic acute leukemia is a pediatric hematological-oncological emergency associated with high morbidity and mortality. Objective. To describe the clinical and hematological characteristics, complications, and treatments of patients with acute hyperleukocytic lymphoblastic or myeloid leukemia. Population and methods. Descriptive, retrospective, cross-sectional study conducted in a tertiary pediatric hospital between January 1, 2020, and December 31, 2024. Results. Twenty-one patients <15 years of age diagnosed with hyperleukocytic leukemia were analyzed. Fifty-six percent had type B acute lymphoblastic leukemia, and 62% had extramedullary manifestations such as hepatomegaly and splenomegaly. The most common complications were tumor lysis syndrome (71%) and leukostasis (28%); 76% received rasburicase, and 1/3 required leukapheresis; 90% began chemotherapy within the first 2 days of hospitalization. There was a single early death due to hemorrhage in the central nervous system. Conclusion. The importance of early diagnosis and intensive initial management to improve the clinical outcomes of these high-risk patients is highlighted.

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

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy of the oral cavity, with increasing incidence and poor prognosis. Myeloid leukemia 1 (Mcl-1), an anti-apoptotic protein in the BCL-2 family, is critical for tumor development and progression. In this study, we investigated Dioscin, a natural compound, as a potential therapeutic agent for OSCC. Our results demonstrated that Dioscin significantly inhibits cell viability and colony formation in OSCC cell lines. Mechanistically, Dioscin induced intrinsic apoptosis by promoting the ubiquitination and degradation of Mcl-1. Further analysis revealed that Dioscin enhances the interaction between the E3 ligase β-TRCP and Mcl-1 by inhibiting the Akt/GSK3β signaling pathway, resulting in increased phosphorylation of Mcl-1 at Ser159, which drives its destabilization. In vivo, Dioscin notably suppressed OSCC tumor growth, including in sensitive and radioresistant cells, by reducing Mcl-1 levels. These findings highlight the therapeutic potential of Dioscin for OSCC treatment, offering new insights for overcoming radioresistance and improving clinical outcomes in OSCC patients.

BACKGROUNDThe ocular manifestations in acute leukemia can occur due to primary leukemic infiltration or secondary to the disease and chemotherapy complications. As the life expectancy has increased in leukemia cases due to the advent of modern chemotherapy, the incidence of ocular features is more evident.AIMTo describe the clinical pattern of ocular manifestations at the time of diagnosis of acute leukemia in children.METHODSThis was a hospital-based, cross-sectional study conducted at a tertiary care academic Institute in eastern India between July 2016 to December 2019. All children below 15 years diagnosed with acute leukemia underwent a comprehensive eye checkup before initiation of chemotherapy. The demographic details, type of leukemia, hematological findings, and chemotherapy regimen were documented.RESULTSAmong the 47 children diagnosed with acute leukemia only 19 cases (40.4%) had ocular involvement. There were 33 boys (70.2%) and 14 (29.8%) girls. Ocular involvement was more common in lymphoblastic leukemia in our study in 13 cases [39.4%; 11 B-acute lymphoblastic leukemia (B-ALL), 2 T-ALL] than in myeloid leukemia in 6 cases (42.9%). The most common manifestation was leukemic retinopathy mainly intraretinal hemorrhages in 12 cases (25.5%; B-ALL-10, and T-ALL-2).CONCLUSIONOphthalmological manifestations are more common in ALL patients (39.4%). Periodic ophthalmic evaluations of all patients must be made to detect ocular findings in asymptomatic cases. Early detection, risk stratification, and regular follow-up are also needed.

Venetoclax/FluBu2 RIC transplant followed by all-oral venetoclax/decitabine maintenance for poor-risk MDS/AML.

Intracranial hemorrhage (ICH) is a fatal complication of leukemia; however, mechanisms underlying its development, particularly central nervous system (CNS) involvement and vascular injury, remain unclear. We aimed to investigate the histopathologic features of cerebral vessels in leukemia and the expression of hemostasis-related factors in leukemia cells. We conducted an autopsy-based study including 37 leukemia cases and 20 matched controls. Histopathologic analysis of CNS tissues was performed to evaluate ICH, leukemia cell localization, and vascular injury. Immunohistochemistry was performed to assess expression of vascular endothelial growth factor (VEGF), cathepsin G, tissue-type plasminogen activator, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and tissue factor in leukemia cells. Vascular integrity was evaluated using stains for smooth muscle actin, collagen, fibrin, and von Willebrand factor. ICH was identified in 68% of leukemia cases and was associated with fatal brain herniation in 40%. CNS involvement was observed in 54% of cases, often without a clinical diagnosis. The leukemia cell infiltration of meninges and vascular walls was frequently associated with changes in smooth muscle cells and adventitial collagen. CNS vascular injury was frequently associated with ICH in the presence of leukemia cell infiltration. VEGF and urokinase-type plasminogen activator were highly expressed in leukemia cells. VEGF was associated with meningeal invasion, while cathepsin G was predominantly expressed in myeloid leukemia and linked to vascular damage. VEGF and cathepsin G may serve as markers of meningeal invasion and cerebral vascular damage in leukemia, respectively.

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

BLOODSTREAM INFECTIONS IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION: FREQUENCY, RISK FACTORS AND RESISTANCE PATTERNS AS A BASIS FOR EMPIRICAL THERAPY

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.

γδ T lymphocytes and NK cells are effective to kill tumors or viral-infected cells avoiding graft versus host disease (GvHD), thus they have attracted high interest as potential tool for adoptive cell therapy. We generated an advanced therapy medicinal product (ATMP) composed of mature γδ T and NK cells to provide an innovative tool to protect patients against tumor relapse and life-threatening infection after haploidentical hematopoietic stem cell transplantation. The ATMP was manufactured and validated in a GMP facility and was obtained from leukapheresis stimulated with zoledronic acid and IL-2, afterward depleted of αβ T lymphocytes using the CliniMACS Prodigy. The ATMP is characterized by high homogeneity, cell viability, cytotoxic abilities, stability after cryogenic preservation, and it was virtually free of αβ T and B lymphocytes. Both NK and γδ T cells were activated and characterized by high expression of cytotoxic and activating receptors including NKG2D, CD16, NKp30, NKp44, and NKp46. Furthermore, γδ T lymphocytes and NK cells were cytotoxic against myeloid leukemia or neuroblastoma cells. In conclusion, we implemented a novel ATMP to be shortly translated into clinical practice, which may be used in the post-transplant phase as efficacious immunotherapy in neuroblastoma and leukemic pediatric patients.

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

IntroductionPediatric acute leukemia is the most common childhood malignancy and one of the leading causes of cancer-related mortality worldwide, particularly, in low- and middle-income countries (LMICs), where treatment abandonment remains a major barrier to survival. Geographic accessibility and socioeconomic conditions are recognized determinants, but their combined influence in Mexico remains understudied. This study evaluated the association between geographic accessibility, socioeconomic factors, and treatment abandonment among children with acute leukemia in south-central Mexico.MethodsA prospective cohort study was conducted in Oaxaca, Puebla, and Tlaxcala from 2021 to 2023, including 574 children under 18 years diagnosed with acute lymphoblastic or myeloid leukemia. Geographic accessibility was estimated using travel distance and time from patients’ residences to referral hospitals, calculated with ORS Tools in QGIS. Socioeconomic variables included public health insurance affiliation, parental education and occupation, and number of siblings. Treatment abandonment was defined per SIOP criteria as failure to initiate or discontinuation of treatment for ≥4 consecutive weeks. Multivariable logistic regression, adjusted for child’s sex, age, year of diagnosis, and leukemia subtype, was used to assess associations.ResultsTreatment abandonment occurred in 16.6% of patients. In multivariable analysis, lack of public health insurance (aOR = 2.83; 95% CI: 1.39-5.76; P < 0.01) and living ≥141 km from the hospital (aOR = 1.68; 95% CI: 1.02-2.74; P = 0.03) were significantly associated with abandonment. Other factors, including number of siblings, maternal education, and fathers’ occupation, were not statistically significant.ConclusionLack of public health insurance and greater distance to the hospital are key determinants of treatment abandonment in children with acute leukemia in south-central Mexico. Expanding insurance coverage, reducing indirect costs, and addressing geographic barriers are critical to improve treatment adherence and survival outcomes in this population.

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.