Clinical characterization and prognosis of T cell acute lymphoblastic leukemia with high CRLF2 gene expression in children

Wang, Mingmin; Wen, Jinquan; Guo, Yuxia; Shen, Yali; An, Xizhou; Hu, Yanni; Xiao, Jianwen

doi:10.1371/journal.pone.0224652

Cited by 4 publications

(5 citation statements)

References 20 publications

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“…The outcomes of T-LBL are improved by ALL-based chemotherapy, but EFS of T-LBL and T-ALL in our study were different. Three-year pEFS exceeded 80% for advanced-stage T-LBL in our study, whereas 3-year pEFS was 54.1 ± 11.2% in the pediatric T-ALL population in our department ( 30 ). This difference was partly due to the different chemotherapy regimens used for the two patient groups, but the different gene distributions of T-ALL and T-LBL also played important roles in the prognosis in our opinion.…”

Section: Discussioncontrasting

confidence: 60%

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing

Liu,

Yu,

Wen

et al. 2023

Front. Pediatr.

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ObjectiveTo investigate the genomic signatures and prognosis of advanced-stage T cell lymphoblastic lymphoma (T-LBL) and to examine the relationship between T-LBL and T cell acute lymphoblastic leukemia (T-ALL).Methods35 Chinese T-LBL children with stage III or IV disease were recruited for this study. They were treated with combination chemotherapy and whole exome sequencing. The relationship of the clinical features, prognosis and specific gene mutations was researched. Gene chips of T-LBL and T-ALL were downloaded from a database, and differential gene expression was analyzed.ResultsGermline causal gene mutations (CARS or MAP2K2) were detected in 2 patients; 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, and the age at diagnosis of patients with NOTCH1-FBXW7 mutations was less than that of patients without such mutations (P < 0.05). 32 patients achieved complete remission (CR), 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, 3 patients relapsed. 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 PI3K-Akt signal pathway genes and the USP34 gene was found in the T-LBL dataset.ConclusionAlthough 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 PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.

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Section: Discussioncontrasting

confidence: 60%

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing

Liu,

Yu,

Wen

et al. 2023

Front. Pediatr.

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“…The criteria for CNSL or testicular leukemia (TL) were defined as described in the literature. The treatment protocol was classified into induction, consolidation, intermediate treatment, reinduction and maintenance treatment [ 11 , 12 ].…”

Section: Methodsmentioning

confidence: 99%

“…The remission status of BM smear samples was recorded as follows: M1 (CR, leukemic cells < 5%), M2 (leukemic cells 5–25%) and M3 (leukemic cells ≥ 25%). Minimal residual disease (MRD) level monitoring was performed by FCM and RT–PCR techniques; 10 –4 was considered the limitation of FCM-MRD monitoring, and negative values were regarded as the cutoff values of PCR-MRD monitoring [ 9 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Enrolled patients received bone marrow (BM) aspiration and/or BM biopsy at initial diagnosis. The diagnosis of B-ALL was based on FAB classification and flow cytometry (FCM); Chromosomal karyotype was evaluated according to the International System of Human Cytogenetic Nomenclature of 2009 (ISCN-2009); interphase FISH of KMT2Ar, ETV6-RUNX1, BCR-ABL1, MYC and PDGFRb were performed as delineated in a literature report [9,10]; common fusion genes, included KMT2Ar transcripts (KMT2A-AFF1, KMT2A-MLLT4, KMT2A-MLLT3, KMT2A-MLLT10, KMT2A-MLLT6, KMT2A-EPS15, KMT2A-MLLT11, KMT2A-FLNA, KMT2A-ELL, KMT2A-MLLT1 and dupKMT2A), were screened by multiplex nested RT-PCR (multiplex RT-PCR) [9][10][11]; Tumor DNA and/or total RNA samples of possible patients were obtained from BM samples at initial diagnosis, whole-exome sequencing (WES) and/or RNA sequencing (RNAseq) were performed by next-generation sequencing (NGS) as found in the literature and as we previously described [9,10]. The positive KMT2Ar transcript results obtained by multiplex RT-PCR and/or RNA-seq were confirmed by split RT-PCR or quantitative real-time RT-PCR (qRT-PCR).…”

Section: Patientsmentioning

confidence: 99%

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Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements

Wen¹,

Zhou

Shen

et al. 2022

BMC Cancer

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Background The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70–75% of infants, 5–6% of children and 10–15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. Methods A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. Results The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT–PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).

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“…Every year, >10,000 new cases of acute lymphocytic leukemia (ALL) in children occur in China, and T-ALL accounts for 15% of them (2)(3)(4)(5). T-ALL is caused by the diffuse bone marrow infiltration of immature T lymphoblasts, which clinically manifests as central nervous system infiltration and mediastinal mass with pleural effusion in the early stage (6). T-ALL is far more difficult to treat than B-ALL and has a poor long-term prognosis (7,8) resulting from poor sensitivity and resistance to chemotherapeutic drugs, issues with remission and clearance of bone marrow microresidual lesions, and a high recurrence rate in the central nervous system (9,10).…”

Section: Introductionmentioning

confidence: 99%

Hirsutanol A inhibits T‑acute lymphocytic leukemia Jurkat cell viability through cell cycle arrest and p53‑dependent induction of apoptosis

et al. 2021

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Acute lymphocytic leukemia (ALL) is a type of childhood leukemia with the highest incidence; T-acute lymphocytic leukemia (T-ALL) is far more difficult to treat than B-acute lymphocytic leukemia (B-ALL) and has a poor long-term prognosis. Therefore, there is an urgent requirement to develop effective drugs for the treatment of T-ALL. Hirsutanol A is a natural sesquiterpenoid compound. The aim of the present study was to evaluate the in vitro anticancer activity of hirsutanol A against T-acute lymphocytic leukemia Jurkat cells and investigate the mechanism of action. A Cell Counting Kit-8 assay demonstrated that hirsutanol A inhibited the viability of Jurkat cells in a dose-and time-dependent manner. In addition, hirsutanol A induced cell cycle arrest at the G 2 phase as determined via flow cytometry. Furthermore, Hoechst staining, Annexin V-FITC/propidium iodide double staining, mitochondrial membrane potential detection using JC-1 and western blot analysis of apoptotic proteins indicated that the inhibitory effect of hirsutanol A on Jurkat cells was associated with the induction of apoptosis. Of note, hirsutanol A induced the expression of the tumor suppressor p53, whereas simultaneous treatment with pifithrin-α, an inhibitor of p53, significantly reduced Jurkat cell apoptosis induced by hirsutanol A. In summary, the present study suggested that hirsutanol A inhibited Jurkat cell viability through induction of cell cycle arrest and p53-dependent initiation of apoptosis, thus hirsutanol may serve as a promising compound for the treatment of T-ALL. By screening a natural compound library owned by State Key Laboratory of Quality Research in Chinese Medicine (Macau, China), it was revealed that hirsutanol A exerted a clear inhibitory effect on the viability of the T-ALL cell line Jurkat. Hirsutanol A is a sesquiterpenoid compound initially

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Clinical characterization and prognosis of T cell acute lymphoblastic leukemia with high CRLF2 gene expression in children

Cited by 4 publications

References 20 publications

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing

Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements

Hirsutanol A inhibits T‑acute lymphocytic leukemia Jurkat cell viability through cell cycle arrest and p53‑dependent induction of apoptosis

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