Background and Aims: To investigate the genomic signatures and prognosis of advanced-stage T cell lymphoblastic lymphoma (T-LBL) and examine the relationship between T-LBL and T cell acute lymphoblastic leukemia (T-ALL). Methods: A total of 35 Chinese T-LBL children with stage III or IV disease were recruited in this study. They were treated with combination chemotherapy, while whole-exome sequencing was performed in these patients. The relationship of the clinical features, prognosis, and specific gene mutations in the cohort was researched. Gene chips of T-LBL and T-ALL were downloaded from a database, and differential gene expression was analyzed. Results: Germline causal gene mutations (CARS or MAP2K2) were detected in 2 patients without a family history of cancer; 3.06±2.21 somatic causal gene mutations were identified in the 35 patients, and somatic mutations were observed in the NOTCH1, FBXW7, PHF6, and JAK3 genes. NOTCH1 mutations were significantly associated with FBXW7 mutations (6/35, 17.14%), and the age at diagnosis of patients with NOTCH1-FBXW7 mutations was younger than that of patients without such mutations (P<0.05). One patient died of sepsis, and treatment-related mortality was 2.86%. Two patients were classified as progressive disease and quit this study, 32 achieved complete remission (CR) for a CR rate of 91.43%, and 14 and 18 patients were classified into the intermediate-risk (IR) group and high risk (HR) group. During a median follow-up of 44 months, three patients relapsed, and the relapse rate was 8.57%. Three-year prospective event-free survival (pEFS) was 82.286%, and no significant differences of pEFS were found for different sexes, ages, or statuses of NOTCH1-FBXW7 mutations (P>0.05); however, the mean survival time of the IR group was longer than that of the HR group (P<0.05). Differential expression of genes in the T-LBL and/or T-ALL datasets was analyzed using the R package limma, and 1/3 of the differentially expressed genes were found in both the T-ALL and T-LBL datasets. High expression of FI3K-Akt signal pathway genes and the USP34 gene was found in the T-LBL dataset. Conclusion: Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the FI3K-Akt signaling pathway and the USP34 gene play essential roles in T-LBL, but medicines targeting the USP34 gene or the FI3K-Akt pathway may be invalid