Dataset Information

Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia.

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common malignant hematological diseases in children. An immunosuppressive microenvironment, particularly regulatory T cell (Treg) infiltration, has been documented to be highly associated with childhood ALL. This present study, based on genetic factors, was aimed at investigating the mutations potentially involved in the immunosuppressive microenvironment in childhood ALL. After whole-exome sequencing was used on DNA extracted from the T cells of ALL bone marrow samples, we found the FOXC1 H446HG induced a increased Treg while decreased cytotoxic T lymphocyte (CTL) in bone marrow. The mutation of FOXC1 in T cell promoted the proliferation of leukemia cells in vitro and in vivo. CpG islands formed by insertion mutation led to an abnormal increase in exon methylation and were associated with the suppression of FOXC1. Decreased FOXC1 attenuated the transcription of HDAC1, thus resulting in the activation of KLF10 through increasing H3K27 acetylation in the promoter region. In conclusion, the de novo insertion mutation in FOXC1 induced suppression of FOXC1, thereby promoting a Treg/CTL shift in the ALL immune microenvironment. The FOXC1 H446HG mutation might be a potential therapeutic target for ALL in the future.

SUBMITTER: Wang Y

PROVIDER: S-EPMC9065155 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia.

Wang Yaping Y Ma Xiaopeng X Huang Jie J Yang Xiaoyun X Kang Meiyun M Sun Xiaoyan X Li Huimin H Wu Yijun Y Zhang Heng H Zhu Yuting Y Xue Yao Y Fang Yongjun Y

Cell death & disease 20220503 5

Acute lymphoblastic leukemia (ALL) is the most common malignant hematological diseases in children. An immunosuppressive microenvironment, particularly regulatory T cell (Treg) infiltration, has been documented to be highly associated with childhood ALL. This present study, based on genetic factors, was aimed at investigating the mutations potentially involved in the immunosuppressive microenvironment in childhood ALL. After whole-exome sequencing was used on DNA extracted from the T cells of AL ...[more]

PMID: 35504885

Similar Datasets

Project description:BackgroundBrain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses.MethodsIn this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment.ResultsPatients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up.ConclusionsBaseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits.ImpactBrain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.

Project description:Background: Advances in treatment and supportive care have significantly improved the overall survival (OS) of pediatric patients with acute lymphoblastic leukemia (ALL). However, there is a large number of these patients who continue to relapse after receiving standard treatment. Accurate identification of patients at high risk of relapse and targeted therapy may significantly improve their prognosis. Therefore, the aim of this study was to identify significant prognostic factors for pediatric ALL and establish a novel nomogram for the prediction of survival. Methods: The ALL clinical data of Phases I and II of the Therapeutic Applicable Research to Generate Effective Treatments (TARGET) project were merged and randomly divided into training and validation groups. The LASSO regression model was used to select the specific factors related to the OS of the training group and generate prognostic nomograms according to the selected characteristics. The predictive accuracy of the nomogram for OS was verified using the concordance index of the training and validation groups, the area under the receiver operating characteristic curve for prognostic diagnosis, and the calibration curve. Results: A total of 1,000 children with ALL were included in the TARGET project. Of those, 489 patients had complete follow-up data for further analysis. The data were randomly divided into the training group (n = 345) and the validation group (n = 144). Seven clinical characteristics, namely age at diagnosis, peripheral white blood cells, bone marrow and CNS site of relapse, ETV6/RUNX1 fusion, TCF3/PBX1, and BCR/ABL1 status, were selected to construct the nomogram. The concordance indices of the training and validation groups were 0.809 (95% confidence interval: 0.766-0.852) and 0.826 (95% confidence interval: 0.767-0.885), respectively. The areas under the receiver operating characteristic curve of the 3-year, 5-year, and 10-year OS in the training group were 0.804, 0.848, and 0.885, respectively, while that of the validation group were 0.777, 0.825, and 0.863, respectively. Moreover, the calibration curves demonstrated a favorable consistency between the predicted and actual survival probabilities. Conclusions: Independent predictors of OS in children with ALL included age at diagnosis, white blood cells, bone marrow site of relapse, CNS site of relapse, ETV6/RUNX1 fusion, TCF3/PBX1, and BCR/ABL1 status. The nomograms developed using these high-risk factors can more simply, accurately, and quantitatively predict the survival of children, and improve treatment and prognosis.

Dataset Information

Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia.

Publications

Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets