Targeted sequencing to identify genetic alterations and prognostic markers in pediatric T-cell acute lymphoblastic leukemia

Chang, Ya‐Hsuan; Yu, Chih-Hsiang; Jou, Shiann-Tarng; Lin, Chien‐Yu; Lin, Kai‐Hsin; Lu, Meng‐Yao; Wu, Kang‐Hsi; Chang, Hong-Yeh; Lin, Dong‐Tsamn; Lin, Shu‐Wha; Chen, Hsuan‐Yu; Yang, Yung‐Li

doi:10.1038/s41598-020-80613-6

Cited by 20 publications

(18 citation statements)

References 54 publications

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“…The PHF6 locus is one of the most frequently mutated genes in T-lymphoblastic leukemia (T-ALL). Inactivating mutations of PHF6 have been identified in 5-16% of pediatric and 19-40% of adult patients with T-ALL and~25% of adults with Tlymphoblastic lymphoma (T-LBL) with some groups identifying an association with NOTCH1 mutations (67%-84.6% of PHF6 mutated/deleted T-ALL with NOTCH1 mutations versus 39.8% PHF6 WT) (4,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Copy number alterations of PHF6 in pediatric T-ALL has been reported to be between 13-14% (39,40).…”

Section: T-lymphoblastic Leukemiamentioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

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Section: T-lymphoblastic Leukemiamentioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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“…Among these pathways, ‘PI3K-Akt signaling pathway’ 18 , ‘Ras signaling pathway’ 19 , ‘MAPK signaling pathway’ 20 , ‘FoxO signaling pathway’ 21 , were related with the development of AML. Additionally, some other pathways such as ‘Pathways in cancer’ 22 , ‘ErbB signaling pathway’ 23 were also tumor related pathways. Genes RUNX1, FLT3, KIT, FASLG, AKT3, MAPK8, GADD45A and PIK3R1 were enriched in greater than or equal to three pathway terms.…”

Section: Resultsmentioning

confidence: 99%

Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network

Sun

Dong

Guo

et al. 2022

Sci Rep

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Cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous disease with different prognoses. Researches on prognostic biomarkers and therapy targets of CN-AML are still ongoing. Instead of protein-coding genes, more and more researches were focused on the non-coding RNAs especially long non-coding RNAs (lncRNAs) which may play an important role in the development of AML. Although a large number of lncRNAs have been found, our knowledge of their functions and pathological process is still in its infancy. The purpose of this research is to identify the key lncRNAs and explore their functions in CN-AML by reconstructing the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA (ceRNA) theory. We reconstructed a global triple network based on the ceRNA theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and published literature. According to the topological algorithm, we identified the key lncRNAs which had both the higher node degrees and the higher numbers of lncRNA–miRNA pairs and total pairs in the ceRNA network. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using databases such as DAVID, KOBAS and Cytoscape plug-in ClueGO respectively. The lncRNA–miRNA–mRNA network was composed of 90 lncRNAs,33mRNAs,26 miRNAs and 259 edges in the lncRNA upregulated group, and 18 lncRNAs,11 mRNAs,6 miRNAs and 45 edges in the lncRNA downregulated group. The functional assay showed that 53 pathways and 108 GO terms were enriched. Three lncRNAs (XIST, TUG1, GABPB1-AS1) could possibly be selected as key lncRNAs which may play an important role in the development of CN-AML. Particularly, GABPB1-AS1 was highly expressed in CN-AML by both bioinformatic analysis and experimental verification in AML cell line (THP-1) with quantitative real‐time polymerase chain reaction. In addition, GABPB1-AS1 was also negatively correlated with overall survival of AML patients. The lncRNA–miRNA–mRNA network revealed key lncRNAs and their functions in CN-AML. Particularly, lncRNA GABPB1-AS1 was firstly proposed in AML. We believe that GABPB1-AS1 is expected to become a candidate prognostic biomarker or a potential therapeutic target.

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“…Sequencing efforts have revealed several genetic alterations in transcription factors and signaling pathways, as well as epigenetic alterations, mistranslations, and the alteration of RNA stability and are shown in Figure 1 and Table 1 [ 34 ]. The most frequent abnormality in T-cell ALL involves NOTCH1 mutations.…”

Section: Novel Approach In T-all Treatmentmentioning

confidence: 99%

“…Originally, such mutations were found in approximately 50% of cases; in current studies, these mutations occur in over 60% of cases, reaching 75% in recent reports. [ 2 , 5 , 14 , 20 , 34 ]. The Notch1 signaling pathway is crucial in the thymus for early T-cell lineage specification, proliferation, and development, and it can be dysregulated through activating mutations (first identified through the finding of a rare chromosomal translocation t(7;9)(q34;q34.3) [ 2 , 20 ].…”

Section: Novel Approach In T-all Treatmentmentioning

confidence: 99%

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

Lato

Przysucha

Grosman

et al. 2021

IJMS

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Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.

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Targeted sequencing to identify genetic alterations and prognostic markers in pediatric T-cell acute lymphoblastic leukemia

Cited by 20 publications

References 54 publications

PHF6 Mutations in Hematologic Malignancies

PHF6 Mutations in Hematologic Malignancies

Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

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