PI3K/AKT pathway-related microRNA variants in childhood acute lymphoblastic leukemia.

BACKGROUND: Dysregulation of microRNAs (miRNAs) targeting genes in the PI3K/Akt pathway has been implicated in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). However, the impact of genetic variants in these miRNAs on ALL susceptibility has not been extensively explored in the Chinese population. METHODS: To address this gap, we conducted a case-control study to evaluate the association between genetic variants in five PI3K/AKT pathway-related miRNAs (miR-149, miR-126, miR-492, miR-612, and miR-423) and childhood ALL susceptibility in the Chinese population. Additionally, we investigated the effects of the rs2292832 mutation on ALL cell proliferation and apoptosis. RESULTS: Our analyses revealed that the miR-149 rs2292832 mutant heterozygous CT genotype was more frequent in the control group than in the ALL cases, indicating a protective effect against ALL (adjusted odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63-0.97, p = .024). Stratification analyses further revealed that the miR-149 rs2292832 CC genotype was associated with an increased risk of childhood ALL in subgroups of older children, females, those with parents who never smoked or drank alcohol, those living in painted houses, those with B-ALL, and those with high-risk ALL. Finally, we observed that the rs2292832 mutation inhibited ALL cell proliferation and induced apoptosis (p = .001), providing a potential mechanism by which this genetic variant may influence ALL susceptibility. CONCLUSION: Our study highlights the significant association between the miR-149 rs2292832 genetic variant and childhood ALL susceptibility in the Chinese population. These findings expand our understanding of the complex genetic landscape underlying ALL and have implications for the development of personalized therapeutic strategies.

Selection of three miRNA signatures with prognostic value in non-M3 acute myeloid leukemia.

BACKGROUND: MiRNAs that are potential biomarkers for predicting prognosis for acute myeloid leukemia (AML) have been identified. However, comprehensive analyses investigating the association between miRNA expression profiles and AML survival remain relatively deficient. METHOD: In the present study, we performed multivariate Cox's analysis and principal component analysis (PCA) using data from The Cancer Genome Atlas (TCGA) to identify potential molecular signatures for predicting non-M3 AML prognosis. RESULT: We found that patients who were still living were significantly younger at diagnosis than those who had died (P = 0.001). In addition, there was a marked difference in living status among different risk category groups (P = 0.022). A multivariate Cox model suggested that three miRNAs were potential biomarkers of non-M3 AML prognosis, including miR-181a-2, miR-25 and miR-362. Subsequently, PCA analyses were conducted to comprehensively represent the expression levels of these three miRNAs in each patient with a PCA value. According to the log-rank test, AML outcome for patients with lower PCA values was significantly different from those with higher PCA values (P < 0.001). Further bioinformatic analysis revealed the biological functions of the selected miRNAs. CONCLUSION: We conducted a comprehensive analysis of TCGA non-M3 AML data, identifying three miRNAs that are significantly correlated with AML survival. PCA values for the identified miRNAs are valuable for predicting AML prognosis.

Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia.

BACKGROUND/AIMS: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response. METHODS: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration. RESULTS: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001). CONCLUSIONS: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia.

Interleukin-2 and Interleukin-8 Gene Polymorphisms and Acquired Aplastic Anemia Risk in a Chinese Population.

BACKGROUND/AIMS: Cytokines IL-2 and IL-8 both participate in immune regulation. However, the relationship between polymorphisms in these two cytokines and the risk of acquired aplastic anemia (acquired AA) has not been explored. METHODS: We selected five SNPs including rs11575812, rs2069772 and rs2069762 of IL-2, rs2227306 and rs2227543 of IL-8. SNaPshot genotyping was used to test the genotypes of IL-2 and IL-8 polymorphisms in a population of 101 acquired AA patients and 165 healthy controls. RESULTS: The rs2069762 G allele appeared to be a protective mutation, but no significant differences were found in other four SNPs. We also found that rs2069762 had an impact on the transcriptional regulation. CONCLUSIONS: It could be assumed that the rs2069762 polymorphism might reduce the risk of acquired aplastic anemia, while the remaining four SNPs might not contribute to susceptibility to acquired AA in a Chinese population.

Polymorphisms of the TGF-ß1 gene and the risk of acquired aplastic anemia in a Chinese population.

Acquired aplastic anemia (AA) is a hematological disease characterized by failure of bone marrow hematopoiesis resulting in pancytopenia. While immune-mediated destruction of hematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired AA, the transforming growth factor-ß1 (TGF-ß1) is crucial in adjusting the immune system. The aim of our study was to investigate the role of TGF-ß1 gene polymorphisms rs1800469 and rs2317130 in susceptibility to acquired AA. Via the approach of SNaPshot, we genotyped rs1800469 and rs2317130 in 101 patients with acquired AA and 165 controls. It derived us to the conclusion that the genotype TT of rs1800469 (C/T) was significantly associated with decreased risk of acquired AA (adjusted OR = 0.39, 95% CI = 0.18-0.83, P = 0.014). Furthermore, this decreased risk was more pronounced among male patients (adjusted OR = 0.35, 95% CI = 0.13-0.95, P = 0.038) and SAA/vSAA (severe AA/very severe AA) patients (adjusted OR = 0.31, 95% CI = 0.12-0.77, P = 0.02) compared with controls in subgroup analysis. However, a significant increased risk was observed in the genotype distributions of rs2317130 for TT genotype (adjusted OR = 2.52, 95% CI = 1.03-6.19, P = 0.04) compared with the CC genotype among the SAA/vSAA patients and controls in the severity stratification analysis. Our results indicated that TGF-ß1 gene polymorphisms might be involved in the munity of acquired AA in a Chinese population. This initial analysis provides valuable clues for further study of TGF-ß1 pathway genes in acquired AA.

Interaction Between IGF1 Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Chinese Children.

BACKGROUND/AIMS: IGF1 is a key regulator in cell proliferation and apoptosis, and the 3' un-translated region (3'UTR) of the gene plays an important role in gene expression. For the first time, we explored the relationship between polymorphisms in the IGF1 3'UTR region and the risk of childhood acute lymphoblastic leukemia (ALL). METHODS: Questionnaires were applied to collect epidemiological data. The genotypes of IGF1 polymorphisms were tested in a population of 744 ALL patients and 1088 cancer-free controls utilizing Taqman. Cell functional studies included real-time PCR, cell culture and transfection and luciferase assays. RESULTS: We found that rs6214 homozygous AA genotype and rs6218 homozygous CC genotype were significantly associated with increased risk of childhood ALL. In addition, rs6218 CC genotype was associated with increased level of IGF1 mRNA in bone marrow, and the mutation in rs6218 led to aberrant binding capacity of hsa-miR-603 and hsa-miR-3941 in the 3'UTR of IGF1. CONCLUSION: Polymorphisms of rs6214 and rs6218 in the 3'UTR of IGF1 are associated with childhood ALL susceptibility, and the polymorphism of rs6218 is related with IGF1 expression at mRNA level.

Allogeneic hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia with intestinal Behçet's disease: A case report.

Behçet's disease (BD) is a rare condition that is seldom associated with hematological malignancies. In this case report, we present the unique case of a 7-year-old girl diagnosed with juvenile myelomonocytic leukemia (JMML) and intestinal BD. The patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT), which resulted in complete remission of both JMML and BD. Our findings suggest that allo-HSCT may be a feasible treatment option for JMML patients with coexisting BD, and holds promise for achieving remission of both illnesses. However, further clinical investigations are needed to validate these findings.

Salvage treatment of ruxolitinib for refractory adenovirus-associated hemophagocytic syndrome post-haploidentical allogeneic stem cell transplantation: a case report.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare complication following hematopoietic stem cell transplantation (HSCT). Currently, there is a lack of consensus recommendations for the treatment of post-transplant HLH. This case report emphasizes the successful utilization of ruxolitinib as a salvage therapy for HLH post-HSCT. The aim is to provide valuable insights into the optimal management of this rare and complex complication. Case Description: We present a case study of an 11-year-old male patient diagnosed with severe aplastic anemia who received a haploidentical HSCT. On the 86th day post-transplantation, the patient developed recurrent fever, hepatomegaly, hypertriglyceridemia, severe pancytopenia, and elevated levels of inflammatory factors and ferritin. Hemophagocytosis was observed in the bone marrow, and subsequent DNA next-generation sequencing identified adenovirus type C infection, leading to a diagnosis of adenovirus-associated HLH. After unsuccessful treatment attempts with cidofovir, dexamethasone, immunoglobulin, plasmapheresis, and etoposide, ruxolitinib was administered. Remarkably, the patient's clinical symptoms rapidly improved, and his test results gradually normalized with ruxolitinib therapy. The adenovirus viral load became undetectable by the 180th day. With continuous remission, ruxolitinib was discontinued on the 137th day post-transplantation, and a 15-month follow-up examination showed no relapse. Conclusions: We present a case of adenovirus-related secondary HLH (sHLH) post-HSCT, which was effectively treated with ruxolitinib. Our case highlights the potential of ruxolitinib as a therapeutic option for patients with viral infections and sHLH. Nonetheless, the safety and efficacy of this innovative treatment should be evaluated in forthcoming large-scale clinical trials.

Modified SMILE (mSMILE) is active in the treatment of pediatric Epstein-Barr virus-associated natural killer/T-cell lymphoma: a single center experience, case series.

Background: The Epstein-Barr virus-associated natural killer (NK) and T-cell lymphoma (EBV + NK/T cell lymphoma) is a severe illness mainly affecting children and young adults, often resulting in a poor prognosis. To date, there is no consensus on an established treatment strategy. This study aims to evaluate the efficacy and safety of the mSMILE (modified steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen in treating EBV+ NK/T-cell lymphoma and to provide insights into potential treatment outcomes. Methods: In this study, we conducted a retrospective analysis of the clinical data and treatment outcomes for patients with EBV + NK/T cell lymphoma treated at Children's Hospital of Nanjing Medical University between July 2017 and January 2022. These patients received at least two cycles of the mSMILE chemotherapy, in which a single dose of pegaspargase was substituted for 7 doses of L-asparaginase per cycle. Results: Eight patients were included in the study: one with extranodal NK/T-cell lymphoma, one with primary nodal NK/T-cell lymphoma, and six with Systemic EBV+ NK/T cell lymphoma of childhood. The results showed that five patients achieved complete remission, two achieved partial remission, and one showed progressive disease, resulting in a complete remission rate of 62.5% and an overall response rate of 87.5%. The 3-year overall survival (OS) and event-free survival (EFS) rates were 87.5% and 75%, respectively. The most common adverse reactions associated with chemotherapy were hematologic toxicities of stages III to IV. Nonhematologic adverse reactions mainly included impaired liver function, infections, and oral mucositis, which were resolved with aggressive anti-infective therapy. Conclusions: Based on our clinical experience, the mSMILE appears to be a safe and effective treatment option for EBV + NK/T-cell lymphoma, meriting further investigation in late-phase clinical trials.

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma.

Neurodevelopmental cell communication plays a crucial role in neuroblastoma prognosis. However, determining the impact of these communication pathways on prognosis is challenging due to limited sample sizes and patchy clinical survival information of single cell RNA-seq data. To address this, we have developed the cell communication pathway prognostic model (CCPPM) in this study. CCPPM involves the identification of communication pathways through single-cell RNA-seq data, screening of prognosis-significant pathways using bulk RNA-seq data, conducting functional and attribute analysis of these pathways, and analyzing the post-effects of communication within these pathways. By employing the CCPPM, we have identified ten communication pathways significantly influencing neuroblastoma, all related to axongenesis and neural projection development, especially the BMP7-(BMPR1B-ACVR2B) communication pathway was found to promote tumor cell migration by activating the transcription factor SMAD1 and regulating UNK and MYCBP2. Notably, BMP7 expression was higher in neuroblastoma samples with distant metastases. In summary, CCPPM offers a novel approach to studying the influence of cell communication pathways on disease prognosis and identified detrimental communication pathways related to neurodevelopment.

Aligning the Cord Blood-Bone Marrow Differences and the Post-transplantation Clinical Manifestations by Single-Cell RNA-Seq.

Cord blood (CB) transplantation is a promising treatment for hematologic malignancies due to its strong graft-versus-leukemia effect and a low incidence of graft-versus-host disease. However, the risk of infection caused by delayed engraftment has limited its clinical application. In this study, we compared the single-cell RNA-seq of CB, bone marrow (BM), and granulocyte colony-stimulating factor primed BM to understand the differences between these grafts from a comprehensive view, and verified some differences in our clinical data of patients receiving transplantation. We focused on the biological features of key cell types involving the hematopoietic reconstitution and immune reconstitution. Based on the comparison of homing signal and differentiation potential of hematopoietic stem/progenitor cells (HSPCs), CB exhibited a lower content of HSPCs with weaker homing ability but higher stemness than BM. In addition, CB had a higher proportion of naïve T cells, while BM had a higher abundance of effector and memory T cells. Notably, the CD4+ naïve T cells in CB were prone to differentiate into Tregs. In response to neoantigens, the immune activation interactions between T cells and antigen-presenting cells were strong in CB, including CD40_CD40LG, IL16_CD4, and so on. In our clinical data, the subpopulation variations of T cells and the status of monocytes after transplantation were consistent with the results of the single-cell RNA-seq study above. CB, as a new birth system, is immature and active; several mechanisms contribute to its good anti-tumor effect, which can be introduced to other grafts. These findings provide insights into the development of new strategies for hematologic malignancies treatment.

Understanding the unique mechanism of ferroptosis: a promising therapeutic target.

Ferroptosis is an iron-dependent form of regulated cell death and is characterized by high concentrations of intracellular lipid peroxide and a redox imbalance in the cells. Ferroptosis shows distinct morphological and biological features compared with other prominent mechanisms of programmed cell death. The distinct characteristics of ferroptosis include the dysfunction of the lipid peroxide repair enzyme glutathione peroxidase 4, the presence of ferrous iron overload, and the lipid peroxidation of polyunsaturated fatty acids. Several other metabolic pathways (including iron, lipid, and amino acid metabolism) and ferritinophagy, as well as transcription factors, can modulate ferroptosis. However, to date, the molecular mechanism of ferroptosis has not been elucidated. This review outlines the discovery, characterization, regulatory mechanisms, and crosstalk of ferroptosis. Further, we have noted the controversial elements in the ferroptosis-related mechanisms. Our inferences may provide a partial reference for developing strategies to regulate ferroptosis.

Cross-cultural adaptation and validation of the PedsQL™ stem cell transplant module in China: A methodological and cross-sectional study.

Background: Hematopoietic stem cell transplantation (HSCT), as a mature technology, has significantly improved the survival rate of children. However, there lack efficient scales to assess the quality of life (QoL) of children with HSCT in China, which has important implications in the care of this population. This study aimed to translate the original English Pediatric Quality of Life Inventory™ (PedsQL™) Stem Cell Transplant Module into a Chinese mandarin version, and evaluate its reliability. Methods: Children of ages 2-18 years who had received HSCT at Children's Hospital of Nanjing Medical University and Children's Hospital of Fudan University were recruited. Children or their parents were asked to fill the PedsQL™ 4.0 Generic Core Scales, PedsQL™ Stem Cell Transplant Module, and PedsQL™ Family Information Form. Feasibility was evaluated by completion rate and the percentage of missing items, reliability by the internal consistency and test-retest reliability, and validity by factor analysis and correlation analysis between the scores of total scale and each dimension. Results: A total of 120 children (mean age 6.37, SD = 3.674) and some parents were included. A low percentage of items were missed in returned reports. Cronbach's alpha coefficient reached 0.70 in the majority of dimensions of both child self-report and parent proxy-report. Test-retest reliability was 0.685 in parents' forms and 0.765 in child's forms. Eight factors were extracted, with a cumulative contribution rate of 74.54%. The correlation between PedsQL™ 4.0 and Transplant Module was 0.748 for children self-report and 0.808 for parent proxy-report. Conclusions: This study provides evidence that the Chinese mandarin version of the PedsQL™ Stem Cell Transplant is feasible, reliable and valid in evaluating the QoL of Chinese children after HSCT.

hOGG1 Ser326Cys polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population.

Oxidative DNA damage caused by reactive oxygen species can produce 8-oxoguanine (8-oxoG) in DNA, which is misread and leads to G:C→T:A transversions. This can be carcinogenic. Repair of 8-oxoG by the base excision repair pathway involves the activity of human 8-oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case-control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49-0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40-0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47-0.99, P = 0.042), and B-phenotype ALL (adjusted OR = 0.63, 95% CI = 0.46-0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population.

Pseudoprogression of extramedullary disease in relapsed acute lymphoblastic leukemia after CAR T-cell therapy.

Background: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy in relapsed or refractory B-cell acute lymphoblastic leukemia. The changes in extramedullary (EM) disease in pediatric relapsed or refractory B-cell acute lymphoblastic leukemia after CAR T-cell therapy have rarely been reported. Materials & methods: A child with relapsed B-ALL was treated with CAR T-cell therapy. Bone marrow morphological examination, minimal residual disease, fusion mutation and radiological evaluation of the EM disease were performed before and after CAR T-cell infusion. Results: Radiological assessment revealed a distinct asymptomatic pseudo progression of EM involvements on day 16 after CAR T-cell infusion. Conclusion: Pseudoprogression of EM disease indicates heterogeneous immune-related patterns of response in patients treated with CAR-T therapy. Such patients should be closely monitored and practical immune-related response criteria should be developed for them.

Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population.

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC/CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (+/-4.38) in cases and 9.27 ng/mL (+/-4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population.

CLAG-M chemotherapy followed by umbilical cord blood stem cell transplantation for primary refractory acute myeloid leukaemia in a child: A case report.

BACKGROUND: The prognosis of paediatric primary refractory/relapsed acute myeloid leukaemia (R/R AML) remains poor. Intensive therapy is typically used as salvage treatment for those with R/R AML. No data are currently available about the use of the CLAG-M protocol as salvage therapy in paediatric patients with R/R AML. CASE SUMMARY: An 8-year-old patient was diagnosed with acute myeloid leukaemia by bone marrow morphology and immunophenotype. The patient showed poor response to two cycles of induction therapy with 60% blast cells in the bone marrow after the second induction cycle. The patient achieved complete remission after being treated with the CLAG-M protocol as salvage therapy before undergoing umbilical cord blood stem cell transplantation. Morphological complete remission with haematological recovery has hitherto been maintained over 4 mo. Abnormal gene mutations detected at diagnosis were undetectable after haematopoietic stem cell transplantation. CONCLUSION: Here we present a paediatric patient with primary refractory acute myeloid leukaemia who was successfully treated with the CLAG-M protocol. Given the positive results of the presented patient, large-scale clinical studies are required to assess the role of the CLAG-M protocol in the salvage treatment of refractory or relapsed AML in childhood.