Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility.

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.

QRICH1 suppresses pediatric T-cell acute lymphoblastic leukemia by inhibiting GRP78.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that commonly affects children and adolescents with a poor prognosis. The terminal unfolded protein response (UPR) is an emerging anti-cancer approach, although its role in pediatric T-ALL remains unclear. In our pediatric T-ALL cohort from different centers, a lower QRICH1 expression was found associated with a worse prognosis of pediatric T-ALL. Overexpression of QRICH1 significantly inhibited cell proliferation and stimulated apoptosis of T-ALL both in vitro and in vivo. Upregulation of QRICH1 significantly downregulated 78 KDa glucose-regulated protein (GRP78) and upregulated CHOP, thus activating the terminal UPR. Co-overexpression of GRP78 in T-ALL cells overexpressing QRICH1 partially reverted the inhibited proliferation and stimulated apoptosis. QRICH1 bound to the residues Asp212 and Glu155 of the nucleotide-binding domain (NBD) of GRP78, thereby inhibiting its ATP hydrolysis activity. In addition, QRICH1 was associated with endoplasmic reticulum (ER) stress in T-ALL, and overexpression of QRICH1 reversed drug resistance. Overall, low QRICH1 expression is an independent risk factor for a poor prognosis of pediatric T-ALL. By inhibiting GRP78, QRICH1 suppresses pediatric T-ALL.

Delineation of features, responses, outcomes, and prognostic factors in pediatric PDGFRB-positive acute lymphoblastic leukemia patients: A retrospective multicenter study.

BACKGROUND: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB-positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. METHODS: This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. RESULTS: Pediatric PDGFRB-positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B-ALL and 4 T-ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31-33 abnormalities, and one suffered from a complex karyotype. The 3-year event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow-up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine-kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p < .05). CONCLUSIONS: Pediatric PDGFRB-positive ALL has a poor outcome associated with high-risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. PLAIN LANGUAGE SUMMARY: Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high-risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine-kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB-positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB-positive ALL patients.

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.

Pan-genome and phylogenomic analyses highlight Hevea species delineation and rubber trait evolution.

The para rubber tree (Hevea brasiliensis) is the world's sole commercial source of natural rubber, a vital industrial raw material. However, the narrow genetic diversity of this crop poses challenges for rubber breeding. Here, we generate high-quality de novo genome assemblies for three H. brasiliensis cultivars, two H. brasiliensis wild accessions, and three other Hevea species (H. nitida, H. pauciflora, and H. benthamiana). Through analyzing genomes of 94 Hevea accessions, we identify five distinct lineages that do not align with their previous species delineations. We discover multiple accessions with hybrid origins between these lineages, indicating incomplete reproductive isolation between them. Only two out of four wild lineages have been introduced to commercial rubber cultivars. Furthermore, we reveal that the rubber production traits emerged following the development of a large REF/SRPP gene cluster and its functional specialization in rubber-producing laticifers within this genus. These findings would enhance rubber breeding and benefit research communities.

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.

Poor outcome in congenital mesoblastic nephroma with TPM3::NTRK1 fusion: a case report from multi-disciplinary treatment to molecular tumor board.

Background: Congenital mesoblastic nephroma (CMN) is a rare renal tumor with good prognosis in children; however, cellular CMN is a special subtype with poor prognosis. The ETV6 fusion gene has been found in some cellular CMNs, whereas CMNs with TPM3::NTRK1 fusion gene have not been reported. This study aims to share the progression and treatment of a case of CMNs with TPM3::NTRK1 fusion gene, in order to provide experience for the diagnosis and treatment of such specific diseases. Case Description: We report a case of CMN with TPM3::NTRK1 fusion gene and a 3-year course of disease that originated during the fetal period. The child experienced rapid tumor progression 22 months after birth, followed by tumor recurrence 3 months after complete resection of CMN. Although traditional chemotherapy could not prevent the tumor progression. The tropomyosin receptor kinase (TRK) inhibitor larotrectinib resulted in significant inhibitory effects on metastatic lesions in the lungs, liver, and peritoneum. However, the patient ultimately died as the tumor became resistant to larotrectinib. Conclusions: CMN, is a rare pediatric renal tumor that warrant prompt surgical management. A watchful waiting approach may allow for aggressive growth of metastatic disease, as seen in this case of cellular CMN with TPM3::NTRK1 fusion gene, TRK inhibitors can play significant roles in the treatment of CMN with TPM3::NTRK1 fusion gene, but we still need to pay attention to the phenomenon of drug resistance to larotrectinib caused by site mutations of TRKA.

Reduced doses of emicizumab achieve good efficacy: Results from a national-wide multicentre real-world study in China.

INTRODUCTION: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear. AIM: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real-world setting. METHODS: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures. RESULTS: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0-30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0-4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0-12.0) and 4.2 (3.0-6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures. CONCLUSION: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full-dose emicizumab is ill affordable.

Identification of a novel MEF2C::SS18L1 fusion in childhood acute B-lymphoblastic leukemia.

PURPOSE: Leukemia-associated fusion genes are closely related to the occurrence, development, diagnosis, and treatment of leukemia. DNA microarrays and second-generation sequencing have discovered multiple B-ALL fusion genes. We identified a novel MEF2C::SS18L1 fusion gene in a child diagnosed with B-ALL. This study investigates the oncogenicity and prognosis of this fusion gene in B-ALL. METHODS: A child with B-ALL who has a MEF2C::SS18L1 fusion is reported as a newly discovered case. Compared the breakpoints, structural domains, clinical phenotypes, and differential expression genes of MEF2C::SS18L1 and MEF2D::SS18.Using "ONCOFUSE" software, the carcinogenicity of MEF2C::SS18L1 is predicted. Using whole transcriptome sequencing, we analyze the breakpoints and the secondary structure of the fusion protein. Further, we compared the structures, differentially expressed genes, and clinical phenotypes of MEF2D and MEF2C fusion genes by DESeq, GO functional enrichment, and flow cytometry immunophenotyping analysis. RESULTS: Whole transcriptome sequencing identified a MEF2C::SS18L1 fusion transcript in a 3-year-old child with B-ALL. The MADS box, MEF structural domain, HJURP_C structural domain, and TAD I structural domain of MEF2C, and the QPGY structural domain of SS18L1, make up the fusion protein. "Oncofuse" found a 0.99 Bayesian probability that the fusion gene drives cancer. The breakpoint positions, fusion protein secondary structures, differentially expressed genes, and clinical characteristics of this patient were identical to those with MEF2D::SS18 fusion gene. CONCLUSION: We identified a novel MEF2C::SS18L1 fusion gene in childhood ALL, which shares similar structural and clinical characteristics with MEF2D::SS18. Further studies with more samples should be conducted in future.

Health-related quality of life in children with childhood acute myeloid leukemia in China: A five-year prospective study.

Purpose: This study aims to identify the key factors influencing health-related quality of life (HRQoL) of pediatric acute myeloid leukemia (AML) patients following their initial diagnosis and examine their impact on the five-year survival prognosis. Methods: A chart review and follow-up were conducted for children with AML who participated in a prospective cohort study between 2017 and 2020. We identified factors influencing HRQoL through Pediatric Quality of Life Inventory™ (PedsQL™ 4.0), PedsQL™ Cancer Module 3.0 (CM 3.0) and PedsQL™ Family Impact Module 2.0 (FIM 2.0), as well as assessed the impact of impaired HRQoL on the overall outcomes of patients. Results: Sixty-four subjects enrolled in the study had complete HRQoL outcome data, and 61 of them completed the 5-year follow-up. In CM 3.0, age was positively associated with parental proxy reports (p = 0.040), whereas divorced families were negatively associated with child self-reports (p = 0.045). A positive medical history correlates with FIM 2.0 (p = 0.025). Residence (p = 0.046), the occupation of caregivers (p = 0.014), disease severity (p = 0.024), and the only child (p = 0.029) exhibited statistically significant associations with the impairment of HRQoL. Impaired HRQoL scores shown by the PedsQL™4.0 parent proxy report (p = 0.013) and FIM 2.0 (p = 0.011) were associated with a reduced 5-year survival rate. Conclusions: This study demonstrated that early impairment of HRQoL in pediatric acute myeloid leukemia patients has predictive value for long-term prognosis. Once validated, these findings may provide some guidance to clinicians treating children with AML.