Uncoupling protein 2 (UCP2) is essential for maintaining redox homeostasis and regulating energy metabolism. Abnormal expression of UCP2 has been associated with various tumors, including leukemia. Genipin (GEN), a specific inhibitor of UCP2, has a long history of use in traditional Chinese medicine. However, the precise role and underlying mechanisms of UCP2 in the inhibition of leukemia cells by GEN remain inadequately understood. This study focuses on the expression levels of UCP2 in myeloid leukemia (ML) and investigates the effects of GEN on the proliferation, mitochondrial function, and energy metabolism of the chronic myeloid leukemia (CML) cell line K562. The expression of UCP2 in clinical samples and cell lines (HL-60, U937, and K562) was confirmed using real-time quantitative polymerase chain reaction (qPCR) and western blot. The effects of GEN on K562 cell viability, morphology, and apoptosis were assessed through a cell counting kit-8 (CCK-8), Wright-Giemsa staining, and an annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) apoptosis detection kit. Additionally, the impact of GEN on mitochondrial function and energy metabolism, including reactive oxygen species (ROS), mitochondrial membrane permeability transition pore (MPTP), lactic acid (LA), oxygen consumption rate (OCR), and adenosine triphosphate (ATP) levels in K562 cells, was also examined. The results showed that UCP2 was differentially expressed in clinical samples from patients with ML. Among the three cell lines examined, K562 cells exhibited a significantly higher expression level of UCP2. Functionally, GEN markedly inhibited K562 cell viability while promoting K562 cell differentiation and apoptosis. Mechanistically, UCP2 mRNA and protein expression levels were inhibited by GEN in K562 cells in a concentration- and time-dependent manner. Additionally, GEN dramatically increased ROS generation and induced mitochondrial MPTP opening in K562 cells. Furthermore, GEN significantly reduced LA production in K562 cells and markedly increased OCR and ATP production. The results suggest that UCP2 is differentially expressed in ML patients and cell lines; GEN, a UCP2 inhibitor, induces mitochondrial damage and metabolic remodeling, thereby inhibiting proliferation and promoting apoptosis in K562 cells, and thus could be suggested as an adjuvant of an antitumor metabolic therapy.

To investigate the expression levels of marginal zone B and B1-cell-specific protein (MZB1) in pan-cancer and its association with patient prognosis and tumor microenvironment (TME). MZB1 expression data, clinicopathological parameters, and survival data from 33 cancer types were extracted from the UCSC database for analyzing the correlations of MZB1 with clinical stage, patient prognosis, immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). MZB1 gene mutations in pan-cancer were assessed using cBioPortal online database, and the value of MZB1 for cancer diagnosis was evaluated using ROC curve analysis. MZB1 expression levels in myeloid leukemia and renal carcinoma cells were detected using RT-qPCR and Western blotting, and the effect of MZB1 knockdown on cell proliferation was examined using EdU assay. MZB1 was significantly overexpressed in 20 cancer types, including kidney renal clear cell carcinoma (KIRC), breast invasive carcinoma, and acute myeloid leukemia. Its expression was associated with TNM stage, clinical stage, overall survival, and progression-free survival in multiple cancers. In most tumors, MZB1 expression was correlated significantly with immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, TMB, and microsatellite instability. Gene amplification was the predominant mutation type of MZB1 in pan-cancer, and MZB1 showed high diagnostic value for skin cutaneous melanoma, KIRC, and head and neck squamous cell carcinoma. MZB1 was highly expressed in different myeloid leukemia cell lines and renal carcinoma cell lines, and MZB1 knockdown significantly suppressed the proliferation of HL60 and 769-P cells. MZB1 is highly expressed in a variety of tumors, and its aberrant expression affects the occurrence and prognosis of many tumors, suggesting its potential as a novel tumor biomarker and immunomodulatory target.

Objective: This study aimed to present epidemiological data on pediatric cancers based on the hospital-based cancer registry (HBCR) at Indonesia’s National Referral Hospital. Material and Methods: This descriptive study analyzed data on pediatric cancers from the HBCR for 2021–2023. Demographical data, including age, gender, diagnosis, and admission year, were extracted from the HBCR data. Univariate data analysis was conducted. Results: This study included 344 patients, consisting of 202 males and 142 females. Of those patients, 92 (26.7%) were admitted in 2021, 142 (41.3%) in 2022, and 110 (32%) in 2023. The highest cancer incidence was observed in patients aged 2–5 years (34.9%) and the lowest in those aged <2 years (11.9%). The three most common reported cancers were lymphoid leukemia (47.4%), myeloid leukemia (11.6%), and retinoblastoma (9.6%). Conclusion: Males predominated over females due to the substantial prevalence of leukemia cases. Most pediatric cancers were observed in those aged 2–5 years. While the distributions of cancer varied by age and gender, leukemia remained the leading pediatric cancer.

Anti-Thymocyte Globulin (ATG) is commonly used to prevent graft-versus-host disease (GVHD), but the optimal dosage and type of ATG remains to be determined. We compared retrospectively the safety and efficacy outcomes of allogeneic transplantation using low-dose ATG-Fresenius (15mg/kg) and ATG-Thymoglobulin (10mg/kg) for GVHD prevention. Ninety-eight patients were included, with 46 in the ATG-T group and 52 in the ATG-F group. The median age was 48 years in the ATG-T group (range 20-71) and 50 years in the ATG-F group (range 18-73). Baseline characteristics were similar, with slightly more HLA mismatched donors and single-agent cyclosporine GVHD prophylaxis use in the ATG-T group. Additionally, the ATG-F group had more myeloid leukemia and myelodysplastic syndrome patients, while the ATG-T group had more lymphoma patients. The cumulative incidence of acute GVHD (aGVHD) grade II-IV and chronic GVHD (cGVHD) showed no significant differences. Multivariate analysis indicated that donor HLA mismatch influenced aGVHD risk significantly (p=0.005), and myeloablative conditioning increased cGVHD risk. Bacteremia and CMV reactivation rates were similar, but EBV DNA viremia was higher in the ATG-T group (22% vs. 8%, p=0.047), with one case of Post-Transplant Lymphoproliferative Disorder (PTLD) in the ATG-T group. Cumulative incidence of overall survival (OS), relapse incidence, non-relapse mortality (NRM) and GVHD free, Relapse free Survival (GRFS) did not significantly differ. This study highlights the safety and efficacy of low-dose ATG-F compared to a relatively high dose ATG-T. Prospective studies are necessary to validate the safety and efficacy of low dose ATG-F for GVHD prevention.

In Philadelphia chromosome-positive (Ph +) leukemia, substitution of threonine at the 315 position of BCR::ABL1 with isoleucine (T315I) induces severe resistance to tyrosine kinase inhibitors (TKIs). Of clinical importance, the substitution of the baseline T315I mutation by methionine (I315M) was reported in a Ph + leukemia patient treated with ponatinib. The resultant T315M mutation induces severe TKI-resistance in a murine Ba/F3 model. Asciminib, an allosteric inhibitor of BCR::ABL1, is reportedly active in ponatinib-resistant patients with the T315I mutation. Although asciminib alone is not active in a murine Ba/F3 model with the T315M mutation, asciminib and ponatinib show synergistic activities. In the present study, we introduced the T315M mutation into the intrinsic BCR::ABL1 gene of two Ph + myeloid and one Ph + lymphoid leukemia cell lines using the CRISPR/Cas9 system to directly verify the utility of the combined asciminib and ponatinib in human models. All three T315M-acquired sublines were more resistant to TKIs including ponatinib than T315I-acquired sublines. Notably, asciminib exhibited a stronger synergistic effect with reduced doses of ponatinib in the T315M-acquired sublines of two myeloid cell lines, but not in the lymphoid cell line. This indicates that the combination of ponatinib and asciminib may have a clinical utility in human Ph + myeloid leukemia.

Obesity is a growing global health concern and has been associated with increased mortality from various cancer types, including hematological malignancies. However, evidence for this association in Asian populations, particularly among Japanese adults, remains limited. Thus, this study aimed to examine the association between obesity and mortality due to hematological malignancies. Data from 97,073 participants in the Japan Collaborative Cohort (JACC) Study were analyzed. The participants were followed for a mean duration of 17 years. Body mass index (BMI) was calculated using self-reported height and weight and categorized as underweight (<18.5 kg/m²), normal-weight (18.5-24.9 kg/m²), overweight (25.0-29.9 kg/m²), and obesity (≥30.0 kg/m²). Mortality data for hematological malignancies were obtained from death certificates. Cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, with adjustments made for demographic, lifestyle, and socioeconomic factors. During follow-up, 479 died from hematological malignancies, including lymphoma (n = 200), multiple myeloma (n = 107), and leukemia (n = 166; 106 myeloid leukemia). Compared with normal-weight individuals, those classified as obese exhibited a significantly higher risk of mortality from all hematological malignancies (HR: 1.78; 95% CI: 1.02-3.11), multiple myeloma (HR: 2.75; 95% CI: 1.09-6.94), leukemia (HR: 2.47; 95% CI: 1.07-5.69), and particularly myeloid leukemia (HR: 3.89; 95% CI: 1.66-9.11). No significant association was observed between BMI and lymphoma-related mortality. Obesity is significantly associated with increased mortality from multiple myeloma and leukemia, especially myeloid leukemia, in Japanese adults. These findings underscore the importance of obesity as a modifiable risk factor for certain hematological malignancies in this population.

Blast crisis (BC) in chronic myelocytic leukemia (CML) typically presents with increased blasts in the bone marrow, showing either myeloid or B-lymphoid phenotypes. We report a rare case of CML-BC with a T/myeloid mixed phenotype localized to the lymph nodes. An 80-year-old woman presented with right axillary lymphadenopathy. PET-CT revealed multiple enlarged lymph nodes. Axillary node biopsy showed proliferation of medium-sized atypical lymphoid-like cells expressing both T-cell and myeloid markers. Both bone marrow and peripheral blood showed no abnormalities. The BCR::ABL1 translocation was detected in both bone marrow and lymph node tissue. Fluorescence in situ hybridization showed positive staining for BCR/ABL1 gene rearrangement. Based on these findings, blast crisis of CML with a T/myeloid mixed phenotype was diagnosed. Following dasatinib therapy, the enlarged nodes regressed. Despite the patient's advanced age, no significant adverse events have been observed during the course of treatment.

In patients with de novo chronic myelocytic leukemia in blast phase (lymphoid and myeloid), the outcomes of transplantation have improved over decades. These favorable outcomes suggest the need for a new therapeutic approach as opposed to the progression from chronic phase to blast phase in patients who have chronic myelocytic leukemia after failure on multiple tyrosine kinase inhibitor therapies.

This study investigated the effects of Homoharringtonine (HHT) on K562 cell proliferation and endoplasmic reticulum (ER) stress. The inhibitory effect of HHT was assessed using the CCK-8 assay to calculate IC50 values. Flow cytometry evaluated cell cycle distribution post-HHT exposure, while Proteostat dye assessed protein aggregation. Expression levels of XBP1s and related markers (BIP, CHOP, IRE1α) were measured to analyze ER stress. Results indicated that HHT significantly reduced K562 cell viability, yielding an IC50 value of 28.53 nM. HHT treatment caused cell accumulation in the G0/G1 phase, indicating cell cycle arrest. It also activated ER stress pathways, leading to increased levels of XBP1s, BIP, and CHOP. The combination of HHT with the ER stress inhibitor 4PBA alleviated HHT-induced ER stress, enhancing its anti-tumor effects. This study demonstrates that HHT inhibits K562 cell proliferation while activating ER stress pathways, suggesting that modulating ER stress may enhance its therapeutic efficacy in myeloid leukemia. Further research is required to elucidate the underlying mechanisms.

Higher mortality risk from lung and hematological neoplasms in patients with rheumatoid arthritis: An observational study from the Spanish National Registry

Platelets are correlated with myeloid leukemia (ML), but to date, there have been no studies confirming the causal relationship between them. Platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW) data were obtained from the GWAS catalog database as exposure factors. Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) data were obtained from the FinnGen database as outcome indicators. The causal relationship between exposure and outcome was explored using the inverse variance weighted, MR-Egger, weighted median, and simple mode methods of dual-sample Mendelian randomization (MR). The stability and reliability of the results were assessed using Cochran's test, MR-Egger regression, and MR-PRESSO methods. An elevated PCT is positively associated with the risk of CML [ORMR-Egger = 2.591, 95% CI (1.089 - 6.166), p = 0.032; ORSimple mode = 9.873, 95% CI (1.112 - 87.646), p = 0.040]. There was no evidence of heterogeneity or plei-otropy at the gene level. However, there were no causal associations between other indices and CML, and none of the four platelet indices were causally associated with AML. An increase in PCT significantly increases the risk of developing CML, making it a candidate biomarker for clinical screening of CML.

In this work, a simple and mild process was used to synthesize a series of 2-amino-4,6-diarylpyrimidine derivatives, 1a-1q, whose structures were verified by FTIR, 1D- and 2D-NMR, and HRMS techniques, to investigate and develop anticancer agents. Under microwave irradiation, a two-step process was carried out, consisting of aldol condensation of benzaldehydes and acetophenones to produce intermediate chalcones and ring closure condensation of chalcones and guanidine hydrochloride. Each generated compound's anticancer activity against the human chronic myelocytic leukemia K562 cancer cell line was investigated in vitro to determine the active compounds, which were subsequently evaluated for inhibiting the ABL1 tyrosine kinase. According to these findings, compound 1e demonstrated considerable inhibition against K562 cancer cells and ABL1 tyrosine kinase at IC50 values of 8.77 ± 0.55 μM and 3.35 ± 0.58 μM, respectively. The molecular docking on wild-type and mutant type ABL1 (PDB ID 2HYY and 5MO4) investigation indicated that 1e and 1g interacted with amino acids. It formed stable hydrogen bonds and π-π linkages with crucial residues in the active site of the enzyme. Moreover, the stability of these enzyme-ligand complexes was confirmed using molecular dynamics simulations. These findings suggested that compounds 1e and 1g can be considered promising cancer treatment agents.

Latar Belakang : Chronic myeloid leukemia (CML) sebagian besar ditemukan pada kelompok usiadewasa dengan rata-rata usia 65 tahun. Meskipun jarang, CML juga dapat terjadi pada usia anak-anakdengan angka insiden rata - rata sebesar 2,5 kasus per juta orang pertahun di dunia. Di Indonesiasendiri, kasus CML anak mencapai 2,7% dari total kasus kanker pada tahun 2020-2024.Kasus : Kami melaporkan seorang anak perempuan berusia 15 tahun yang datang dengan keluhanlemas sejak 3 hari sebelum dibawa ke rumah sakit dan sudah berulang 5 tahun terakhir ini. Keluhandisertai rambut sering rontok, berat badan tidak naik, perut semakin membesar, kulit terlihat menghitamsetiap hari dan demam berulang tanpa sebab yang jelas. Dari alloanamnesis ditemukan paman pasienmengalami keluhan serupa. Pemeriksaan fisik didapatkan kedua konjungtiva anemis dan splenomegali.Pemeriksaan hematologi didapatkan anemia, leukositosis dengan sel blast 9% dan trombositosis. Hasilpemeriksaan molekuler BCR ABL didapatkan positif dari fusi gen BCR ABL exon e14a2, sehinggapasien di diagnosis sebagai chronic myeloid leukemia phase kronis. Pasien dirawat di rumah sakit sertadiberikan terapi cairan dan Imatinib. Background : Chronic myeloid leukemia (CML) is primarily found in adults, with an average age of 65years. Although rare, it can also occur in children, with an average incidence of 2.5 cases per millionpeople per year worldwide. In Indonesia, 2.7% of total cancer cases between 2020 and 2024 waspediatric CML.Case : We report a 15-year-old girl who came to hospital with complaints of weakness for three daysprior to hospitalization, which had recurred over the past five years. Associated symptoms includedfrequent hair loss, no weight gain, abdominal distension, daily skin darkening, and recurrent feverwithout a clear cause. Family history revealed similar complaints were found in the patient's uncle.Physical examination showed conjunctival pallor and splenomegaly. Anemia, leukocytosis with 9% blastcells, and thrombocytosis were found in hematological test. Molecular testing for BCR ABL fusion genewas positive for BCR ABL exon e14a2, leading to a diagnosis of chronic myeloid leukemia at chronicphase. The patient was hospitalized and was given fluid therapy and Imatinib

Leukemic microenvironment has been recognized as a factor that strongly supports the mechanisms of resistance. Therefore, targeting the microenvironment is currently one of the major directions in drug development and preclinical studies in leukemia. Despite the variety of available leukemia 3D culture models, the reproducible generation of miniaturized leukemic microenvironments, suitable for high-throughput drug testing, has remained a challenge. Here, we use droplet microfluidics to generate tens of thousands of highly monodisperse leukemic-bone marrow microenvironments within minutes. We employ gelatin methacryloyl (GelMA) as a model extracellular matrix (ECM) and tune the concentration of the biopolymer, check the impact of other components of the ECM (hyaluronic acid), cell concentration and the ratio of leukemic cells to bone marrow cells within the microbeads to establish the optimal conditions for microtissue formation. We administer model kinase inhibitor, imatinib, at various concentrations to the encapsulated leukemic microtissues, and, via comparing mono- and co-culture conditions (cancer alone vs cancer-stroma), we find that the stroma-leukemia crosstalk systematically protects the encapsulated cells against the drug-induced cytotoxicity. With that we demonstrate that our system mimics the physiological stroma-dependent protection. We discuss applicability of our model to (i) studying the role of direct- or close-contact interactions between the leukemia and bone marrow cells embedded in microscale 3D ECM on the stroma-mediated protection, and (ii) high-throughput screening of anti-cancer therapeutics in personalized leukemia therapies.

Abstract Increased extracellular DNA (exDNA) levels in the blood are a hallmark of metastatic cancer, arising from tumor lysis, apoptosis, necrosis, and neutrophil extracellular traps (NETs) released by tumor-expanded neutrophils. NETs, web-like chromatin structures extruded by neutrophils to trap pathogens, are highly immunogenic due to their DNA and histone content and their persistent interaction with dendritic cells. Tumor cells can also release extracellular traps. In myeloid leukemia, blasts release nuclear content via traps to activate coagulation or sustain myeloproliferation. Extracellular traps have been found in NPM1 mutant AML patients, with mutant NPM co-localizing with histones along exDNA traps. Forcing trap extrusion in NPM mutant leukemia cells has been used to create dendritic cell-based vaccines that break tolerance against NPMc antigens. This suggests that NETs in the tumor microenvironment (TME) may promote tolerance, with breaking tolerance requiring consistent NET formation and dendritic cell interaction. NETs are also seen in solid tumors, such as triple-negative breast cancer (TNBC), where they aid in cancer cell migration, invasion, and awakening of circulating tumor cells. However, the capacity of tumor cells to directly extrude DNA traps is not fully understood. To investigate this, various human and murine breast cancer cell lines were seeded on poly-D-lysine coated slides, stained with DAPI and Sytoxgreen, and observed via confocal microscopy. Tumor cells extruded DNA traps within 4 hours without stimuli. Notably, trap extrusion correlated with cell line aggressiveness and was abolished by DNase, indicating dsDNA composition. The absence of traps in 24-hour cultures suggests DNA extrusion may help rare tumor cells survive and proliferate. In line, DNase treatment reduced tumor proliferation and increased apoptosis. To assess the significance of DNA traps in vivo, BALB/c mice were injected with the highly metastatic 4T1 clone 5 breast cancer model, with or without DNase treatment, and monitored starting 5 days post-injection and weekly until day 28. Histological analysis at the injection site 5 days post-injection showed that DNase treatment reduced both local trap formation and tumor cell proliferation, as indicated by BrdU incorporation. Moreover, immunohistochemistry revealed that in DNase-treated mice, initial tumor growth was followed by complete tumor regression, accompanied by local and systemic CD8 T cell activation. Correspondingly, although a few metastases were detectable at day 14 in DNase-treated mice, no metastases were observed by day 28. Although it remains unclear whether tumor-derived or immune cell-derived traps are most relevant in our model, the results demonstrate that their presence in the TME promotes tolerance despite the inherent immune adjuvant properties of the traps. This suggests that DNase treatment could be particularly effective in combating early tumor development or relapse when used as part of a combination therapy designed to sustain anti-tumor immune responses. Citation Format: Sabina Sangaletti, Paola Portararo, Laura Botti, Valeria Cancila, Claudio Tripodo, Mario P. Colombo, Claudia Chiodoni. Degradation of extracellular trap DNA sustains anti-tumor immune responses in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C014.

Long-Term Follow-up of Bendamustine/Rituximab - Rituximab/Cytarabine (BR/RC) Induction Therapy for Previously Untreated Transplant-Eligible Patients with Mantle Cell Lymphoma (MCL)

The Impact of July Admission on Outcome in Patients with Hematopoietic and Lymphoid Malignancy Admitted with Tumor Lysis Syndrome

Early CMV Viral Load Burden Predicts Late Clinically Significant CMV Infections in Patients Receiving Ptcy-Based Hematopoietic Cell Transplantation

Roles of TET2 Loss in B Cell Transformation

Cyclophosphamide, an immunosuppressive alkylating agent, has been used against breast cancer, lymphoma and myeloid leukemia. Despite various therapeutic uses, its toxic impacts on multiple organs remains to be fully elucidated. This study aimed to investigate dose dependent toxic impact of cyclophosphamide on liver, kidney, brain and testis emphasizing serum and tissue biochemical and histological alterations. Experimental design consisted of five groups of albino rats. Group 1-5 were administered vehicle for five consecutive days. On 6th day, group 1 received vehicle only and termed as control; group 2-5 received cyclophosphamide through intraperitoneal route at the rate of 50, 100, 150 and 200mg/kg dose, respectively. After 24h of the last administration, rats were euthanised; serum and tissue biochemistry; histology, sperm count and its motility were performed. Serological, biochemical and histological indices exhibited dose dependent deviations from their regular status as a marker of toxicity in liver, kidney, brain and testis. Tukey's HSD post hoc test revealed maximum damage in multiple organs with 200mg/kg dose of cyclophosphamide.