BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

Copy number alteration (CNA) is a significant genetic change in pediatric B-cell acute lymphoblastic leukemia (B-ALL), with CDKN2A/B deletions, PAX5 deletions, and IKZF1 deletions being the most common. Recent studies have increasingly highlighted the potential prognostic significance of these gene deletions and multiple co-deletions in pediatric B-ALL. This paper reviews the main detection methods for CNA, as well as the prognostic characteristics and treatment approaches for common CNA in pediatric B-ALL.
Humans ; DNA Copy Number Variations ; Child ; PAX5 Transcription Factor/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Cyclin-Dependent Kinase Inhibitor p15/genetics* ; Ikaros Transcription Factor/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Gene Deletion ; Cyclin-Dependent Kinase Inhibitor p16/genetics* ; Prognosis

OBJECTIVES: To investigate the effects of methylenetetrahydrofolate reductase (MTHFR) rs1801133 and γ-glutamyl hydrolase (GGH) rs11545078 gene polymorphisms on plasma concentrations and toxicity following high-dose methotrexate (MTX) therapy in children with acute lymphoblastic leukemia (ALL). METHODS: Children with ALL treated at the Xuzhou Children's Hospital of Xuzhou Medical University from January 2021 to April 2024 were selected for this study. Genotypes of MTHFR rs1801133 and GGH rs11545078 were determined using multiplex polymerase chain reaction. MTX plasma concentrations were measured by enzyme-multiplied immunoassay technique, and toxicity was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The relationships between MTHFR rs1801133 and GGH rs11545078 genotypes and both MTX plasma concentrations and associated toxicities were analyzed. RESULTS: In the low-risk ALL group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 72 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05), and the GGH rs11545078 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with the occurrence of reduced hemoglobin (P<0.05), and the GGH rs11545078 genotype was associated with the occurrence of thrombocytopenia (P<0.05). CONCLUSIONS Detection of MTHFR rs1801133 and GGH rs11545078 genotypes can be used to predict increased MTX plasma concentrations and the occurrence of toxic reactions in high-dose MTX treatment of ALL, enabling timely interventions to enhance safety.
Humans ; Methotrexate/toxicity* ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood* ; Male ; Female ; Child ; Child, Preschool ; gamma-Glutamyl Hydrolase/genetics* ; Antimetabolites, Antineoplastic/adverse effects* ; Infant ; Polymorphism, Genetic ; Adolescent ; Genotype ; Polymorphism, Single Nucleotide

OBJECTIVE: To investigate the expression of long non-coding RNA plasmacytoma variant translocation 1 (lncRNA-PVT1) in children with acute lymphoblastic leukemia (ALL) and its correlation with prognosis. METHODS: Clinical data of 64 children with ALL were retrospectively analyzed. All children received standardized treatment according to CCLG-ALL-2015 protocol, and their overall survival (OS) was followed up. Bone marrow examination and lncRNA-PVT1 examination were performed before first diagnosis (T1), early intensive therapy (T2), consolidation therapy (T3), delayed intensive therapy (T4), and maintenance therapy (T5). Bone marrow samples of 25 children with thrombocytopenic purpura were collected during the same period as control group. LncRNA-PVT1 expression was compared between ALL group and control group. ALL children were divided into high-risk group and non-high-risk group according to the risk factors at T3, and the expression changes of lncRNA-PVT1 were analyzed. The correlation of lncRNA-PVT1 with clinical features and prognosis of ALL children was analyzed. RESULTS: The expression of lncRNA-PVT1 in ALL children was significantly higher than that in control group (P < 0.001). ROC curve analysis showed that the area under curve (AUC) of lncRNA-PVT1 for ALL diagnosis was 0.919(95%CI : 0.863-0.975), the optimal cut-off value was 1.465, sensitivity was 87.50%, and specificity was 98.80%. ALL children were divided into low lncRNA-PVT1 group (lncRNA-PVT1< 2.18) and high lncRNA-PVT1 group (lncRNA-PVT1≥2.18) according to the median lncRNA-PVT1 value (2.18). The high lncRNA-PVT1 group had higher Day 33 MRD compared with low lncRNA-PVT1 group (P < 0.01). At T3, T4 and T5, the expression of lncRNA-PVT1 in high-risk group was significantly higher than that in non-highrisk group (all P < 0.01). The expression of lncRNA-PVT1 were significantly increased in high-risk group at 5 time points (P < 0.001), while, there was no significant difference in non-high-risk group (P >0.05). The median OS of low lncRNA-PVT1 group was 35(9-37) months, which was significantly higher than 25(5-33) months of high lncRNA-PVT1 group (P < 0.01). Univariate and multivariate Cox regression analysis showed that Day 33 MRD (>10^-2) and lncRNA-PVT1 (≥2.18) were independent risk factors for OS in ALL children (both P < 0.05). CONCLUSION LncRNA-PVT1 is involved in the pathogenesis of ALL in children and closely related to the prognosis.
Humans ; RNA, Long Noncoding/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis* ; Prognosis ; Retrospective Studies ; Child ; Male ; Female ; Child, Preschool ; Adolescent

OBJECTIVE: To explore the clinical characteristics, therapeutic responses and prognostic features of E2A-PBX1 fusion gene for childhood acute lymphoblastic leukemia (ALL). METHODS: A total of 837 pediatric patients with ALL who were initially diagnosed in our hospital from July 2010 to November 2017 were retrospectively analyzed, 48 children with positive E2A-PBX1 fusion gene were detected by the real-time quantitative PCR techniques and their data were retrospectively collected for analysis. RESULTS: Among 48 cases with positive E2A-PBX1 fusion gene, there were 26 males and 22 females, with onset ages ranging from 9 months to 13 years old. There were 2 cases (4.2%) in the low-risk group, 32 cases (66.7%) in the intermediate-risk group, and 14 cases (29.1%) in the high-risk group at initial diagnosis. The white blood cell (WBC) counts of 25 cases (53.2%) at initial diagnosis were <50×10⁹/L, 11 cases (23.4%) were (50-100)×10⁹/L, and 11 cases (23.4%) ≥100×10⁹/L. The main immunophenotype was common-B ALL (44 cases, 91.7%). Other leukemia fusion genes such as BCR-ABL1, MLL-AF4, and TEL-AML1 were not observed in this cohort of patients. All patients received the treatment of NPCLC-ALL2008 protocol, and 5 cases (10.4%) occurred poor prednisone response. All the 48 cases achieved complete remission (CR) after the induction treatments. The last follow-up date was April 30, 2023. A total of 5 children relapsed, including 1 case with intermediate risk and 4 cases with high risk. The recurrence rate in the high-risk group was significantly higher than that in the intermediate- and low-risk groups (both P < 0.05). Most relapsed children had elevated WBC counts at initial diagnosis. Among them, WBC counts ≥100×10⁹/L was observed in 4 cases. The recurrence rate among children with WBC counts ≥100×10⁹/L was significantly higher than that with WBC counts <100×10⁹/L (P < 0.01). Four deaths occurred in this cohort, of which 3 died of leukemia recurrence. The 10-year event-free survival rate and 10-year overall survival rate of the 48 children with positive E2A-PBX1 fusion gene were 87.5%±4.8% and 91.7%±4.0%, respectively. CONCLUSION In ALL children with positive E2A-PBX1 fusion gene, those with elevated WBC counts and high risk stratification at initial diagnosis are more likely to experience recurrence. Recurrence is the main cause of death in this group. It is suggested that such kind of children receive more intensive chemotherapy or undergo hematopoietic stem cell transplantation as early as possible to further improve prognosis.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis* ; Oncogene Proteins, Fusion/genetics* ; Prognosis ; Child ; Male ; Female ; Child, Preschool ; Adolescent ; Retrospective Studies ; Infant ; Homeodomain Proteins

OBJECTIVE: To investigate the clinical characteristics and prognostic of venetoclax (VEN) combined targeted therapy in acute leukemia (AL) patients with PICALM∷MLLT10 fusion gene positivity. METHODS: A retrospective analysis was conducted on 16 PICALM∷MLLT10-positive AL patients treated at the First Affiliated Hospital of Soochow University from January 2021 to August 2024. These patients were diagnosed by targeted RNA sequencing (RNA-seq) or reverse transcription multiplex PCR, including newly diagnosed and relapsed/refractory (R/R) cases. The immunophenotypes, genetic features, gene mutations, and the efficacy of VEN combination targeted therapy of patients were evaluated. RESULTS: Among the 16 cases, 3 were confirmed by reverse transcription multiplex PCR, and 13 were detected through targeted RNA-seq among 528 AL patients, with a detection rate of 2.46%. The averge age of patients was (28.0±8.58) years. Patients exhibited diverse immunophenotypes, including 7 cases of acute myeloid leukemia, 5 of acute T-lymphoblastic leukemia, 1 of acute B-lymphoblastic leukemia, 1 of acute undifferentiated leukemia, and 2 of mixed-phenotype acute leukemia. Among them, 11 had extramedullary disease (EMD), 14 expressed CD7, and 12 expressed CD33. Major co-occurring mutations included PHF6 (6 cases), NOTCH1 (5 cases), and 7 cases with complex karyotypes. Of the 12 patients who received standard induction therapy, 7 did not achieve remission (PR+NR). All 4 patients treated with VEN combination therapy achieved complete remission (CR). Among the 7 induction failure cases, 4 achieved CR upon re-induction with VEN, while the remaining 3 re-induced with standard therapy, did not achieve CR. Thirteen patients received allogeneic hematopoietic stem cell transplantation, including 6 who received maintenance therapy with hypomethylating agents (HMA) alone or in combination with VEN, and seven were followed up. Survival analysis showed that the overall survival was better in the maintenance therapy group (P =0.044). CONCLUSION PICALM∷MLLT10-positive AL involves multiple lineages and demonstrates poor response to conventional chemotherapy. VEN combination therapy shows promising efficacy in both newly diagnosed and R/R patients. Post-transplant maintenance therapy with HMA alone or combined with VEN may extend survival; however, further clinical validation is required.
Humans ; Sulfonamides/therapeutic use* ; Retrospective Studies ; Prognosis ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Adult ; Male ; Female ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*

OBJECTIVE: To analyze clinical characteristics and prognosis of B-cell acute lymphoblastic leukemia (B-ALL) patients with IKZF1 deletion. METHODS: 72 patients with B-ALL admitted to our hospital from April 2020 to January 2023 were selected, IKZF1 deletion were detected, and clinical characteristics and prognosis were analyzed. RESULTS: Among the 72 patients, a total of 32 patients (44.4%) were identified with IKZF1 deletions (IKZF1 ⁺ ). There was no statistically significant difference in basic clinical data between patients with normal IKZF1 (IKZF1 ^-) and those with IKZF1 ⁺ (P >0.05). The proportion of patients with IKZF1 ⁺ in Ph⁺ group was significantly higher than that in Ph^- group (P < 0.05). The main types of IKZF1 ⁺ were exon 1-8 deletion (34.4%) and exon 4-7 deletion (31.2%). The median OS and PFS of IKZF1 ^- patients were significantly longer than those of IKZF1 ⁺ patients (OS: 26.0 months vs 16.0 months, χ ²=23.094, P < 0.05; PFS: 26.0 months vs 16.0 months, χ ²=11.150, P < 0.05). Among IKZF1 ⁺ patients, the median OS of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) was significantly longer than that of patients who did not receive allo-HSCT (no reached vs 15.0 months, χ ²=5.685, P < 0.05). CONCLUSION IKZF1 deletion is a risk factor affecting the prognosis of B-ALL patients.
Humans ; Ikaros Transcription Factor/genetics* ; Prognosis ; Gene Deletion ; Female ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Adult ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Adolescent ; Young Adult ; Middle Aged

OBJECTIVE: To explore the correlation between single nucleotide polymorphisms (SNPs) of ARID5B gene and the risk of acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD) in children of Hui and Han nationality in Ningxia. METHODS: In this case-control study, 54 ALL children and control group with matched age, sex and nationality were detected for the polymorphism of ARID5B gene using fluorescence resonance energy transfer technique, and the susceptibility of different ALL genotypes and their correlation with MRD were analyzed. RESULTS: There were no significant differences in genotype and allele frequency of rs10994982, rs7089424, rs10740055, rs7073837, rs4245595 and rs7090445 between the two groups (P >0.05). At the locus of rs10821936, the frequencies of T/T genotype and T allele in ALL group were significantly higher than those in the control group (both P < 0.05). The C/C genotype of ARID5B gene SNP rs10821936 was a risk factor for early MRD positive in ALL children ( P < 0.05). CONCLUSION ARID5B gene SNP rs10821936 is related to the development of childhood ALL and MRD.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Polymorphism, Single Nucleotide ; Case-Control Studies ; Neoplasm, Residual/genetics* ; DNA-Binding Proteins/genetics* ; Transcription Factors/genetics* ; Genotype ; Genetic Predisposition to Disease ; Gene Frequency ; Child ; Male ; Female ; Alleles ; Risk Factors ; Child, Preschool

OBJECTIVES: To study the clinical characteristics and prognosis of T-lineage acute lymphoblastic leukemia (T-ALL) and related prognostic factors. METHODS: A retrospective analysis was conducted on the children with T-ALL who were treated with the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL) regimen in Guangzhou Women and Children's Medical Center between April 2015 and December 2022. RESULTS: A total of 80 children were included, with a median age of 7 years and 3 months and a male/female ratio of 6:1. Among these children, the children with mediastinal mass accounted for 20% (16/80), those with central nervous system leukemia accounted for 4% (3/80), and those with testicular leukemia accounted for 1% (1/69). SIL/TAL1 was the most common fusion gene (22%, 18/80), and NOTCH1 was the most common mutation gene (69%, 37/54). The median follow-up time was 52 months, with a 5-year overall survival (OS) rate of 87.3%±4.0% and a 5-year event-free survival rate of 84.0%±4.3%. The non-central nervous system-1 group had a significantly lower 5-year OS rate than the central nervous system-1 group (66.7%±16.1% vs 90.3%±3.8%; P<0.05), and the group with minimal residual disease (MRD) ≥0.01% on day 46 of induction therapy had a significantly lower 5-year OS rate than the group with MRD <0.01% (68.6%±13.5% vs 94.8%±3.0%; P<0.05). CONCLUSIONS Children treated with the CCCG-ALL regimen tend to have a good treatment outcome. Non-central nervous system-1 status and MRD ≥0.01% on day 46 of induction therapy are associated with the poor prognosis in these children.
Humans ; Male ; Female ; Child ; Prognosis ; Child, Preschool ; Retrospective Studies ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Infant ; Adolescent ; Receptor, Notch1/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Survival Rate

Objective: To analyze the survival and influencing factors of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) . Methods: Clinical information of patients who received CAR-T-cell therapy and achieved complete remission of R/R B-ALL between May 2015 and June 2018 at the Shaanxi Provincial People's Hospital was obtained. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and leukemia-free survival (LFS) times of patients, and Cox regression analysis was performed to analyze the prognostic factors that affect patient survival after CAR-T therapy. Results: Among the 38 patients with R/R B-ALL, 21 were men, with a median age of 25 (6-59) years and a median OS time of 18 (95% CI 3-33) months. Multivariate Cox regression analysis showed that positive MLL-AF4 fusion gene expression was an independent risk factor for OS and LFS (OS: HR=4.888, 95% CI 1.375-17.374, P=0.014; LFS: HR=6.683, 95% CI 1.815-24.608, P=0.004). Maintenance therapy was a protective factor for OS and LFS (OS: HR=0.153, 95% CI 0.054-0.432, P<0.001; LFS: HR=0.138, 95% CI 0.050-0.382, P<0.001). In patients with MRD negative conversion, LFS benefit (HR=0.209, 95% CI 0.055-0.797, P=0.022) and OS difference was statistically insignificant (P=0.111). Moreover, patients with high tumor burden were risk factors for OS and LFS at the level of 0.1 (OS: HR=2.662, 95% CI 0.987-7.184, P=0.053; LFS: HR=2.452, 95% CI 0.949-6.339, P=0.064) . Conclusion: High tumor burden and high-risk genetics may affect the long-term survival rate of patients with R/R B-ALL receiving CAR-T, and lenalidomide-based maintenance therapy may improve their prognosis.
Male ; Humans ; Adult ; Middle Aged ; Female ; Receptors, Chimeric Antigen/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Immunotherapy, Adoptive ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Cell- and Tissue-Based Therapy