Targeting steroid resistance in T-cell acute lymphoblastic leukemia

Smedt, Renate De; Morscio, Julie; Goossens, Steven; Vlierberghe, Pieter Van

doi:10.1016/j.blre.2019.100591

Cited by 26 publications

(13 citation statements)

References 147 publications

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“…T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive, highly heterogeneous type of lymphoid malignancy, accounting for approximately 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. T-ALL arises from T-cell precursors (thymocytes) during their maturation in the thymus upon accumulation of numerous genetic lesions and cooperating aberrations affecting epigenetic and post-transcriptional regulation of gene expression [1][2][3][4][5][6]. Thus, T-ALL is characterized by a multiplicity of chromosomal rearrangements, copy number alterations, and sequence mutations, leading to activation of oncogenes and inactivation of tumor suppressor genes, which ultimately result in altered gene expression profiles, as a consequence of triggering of oncogenic pathways and transcriptional programs [5,6].…”

Section: Introductionmentioning

confidence: 99%

hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro

Drobna

Szarzyńska

Jaksik

et al. 2020

Cells

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy arising from T lymphocyte precursors. We have previously shown by miRNA-seq, that miRNAs from the mir-106a-363 cluster are overexpressed in pediatric T-ALL. In silico analysis indicated their potential involvement in the regulation of apoptosis. Here, we aimed to test the hypothesis on the pro-tumorigenic roles of these miRNAs in T-ALL cells in vitro. We demonstrate, for the first time, that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster, when upregulated in T-ALL cells in vitro, protect leukemic cells from apoptosis, enhance proliferation, and contribute to growth advantage. We show, using dual luciferase reporter assays, Ago2-RNA immunoprecipitation, RT-qPCR, and Western blots, that the oncogenic effects of these upregulated miRNAs might, at least in part, be mediated by the downregulation of two important tumor suppressor genes, PTEN and BIM, targeted by both miRNAs. Additionally, we demonstrate the cooperative effects of these two miRNAs by simultaneous inhibition of both miRNAs as compared to the inhibition of single miRNAs. We postulate that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster might serve as oncomiRs in T-ALL, by contributing to post-transcriptional repression of key tumor suppressors, PTEN and BIM.

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Section: Introductionmentioning

confidence: 99%

hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro

Drobna

Szarzyńska

Jaksik

et al. 2020

Cells

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“…In terms of signaling pathways, RAS/MEK/ERK, IL7R/JAK/STAT, and PI3K/AKT signaling have been found to be associated with glucocorticoid resistance. Currently, inhibitors targeting these signaling pathways, i.e., MEK inhibitors, AKT inhibitors, and JAK inhibitors, are being tested in clinical trials ( 18 ). Nevertheless, the mechanism underlying glucocorticoid resistance remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Gene Mutations Related to Glucocorticoid Resistance in Pediatric Acute Lymphoblastic Leukemia

et al. 2022

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ObjectiveTo investigate the correlation between gene mutations and glucocorticoid resistance in pediatric acute lymphoblastic leukemia (ALL).MethodsA total of 71 children with ALL admitted to our center between September 2019 and September 2021 were enrolled. DNA obtained from bone marrow or peripheral blood samples at initial diagnosis was used for genetic testing via whole exome sequencing. Meanwhile, patient clinical information was collected. Subsequently, the correlations of gene mutations with clinical features and glucocorticoid resistance were analyzed.ResultsOf the 71 children enrolled, 61 (85.9%) had B-cell ALL (B-ALL) and 10 (14.1%) had T-cell ALL (T-ALL). The five genes with the highest mutation frequency in B-ALL were TTN (24.4%), FLT3 (14.6%), TP53 (14.6%), MUC16 (9.8%), and EPPK1 (9.8%). In contrast, those with the highest frequency in T-ALL were NOTCH1 (54.5%), FBXW7 (27.3%), TTN (27.3%), MUC16 (27.3%), and PHF6 (18.2%). Upon statistical analysis, TTN and NOTCH1 mutations were found to be associated with prednisone resistance. Further, TTN and MUC16 mutations were associated with a lower age at diagnosis, and NOTCH1 mutations were associated with T-ALL in female patients. Leukocyte counts and LDH levels did not differ based on the presence of any common gene mutation, and no association between these gene mutations and overall survival was observed.ConclusionsOur study is the first to demonstrate the association between TTN mutation and glucocorticoid resistance in ALL. Our findings could guide strategies for overcoming drug resistance and aid in the development of drug targets.

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“…It is beyond the scope of this manuscript to discuss the different available therapies for relapsed and refractory patients, although these have been reviewed in other recent publications. 1,32,33 We recommend that all patients receive routine cytogenetic testing and fluorescence in situ hybridization for BCR-ABL1. We also recommend more comprehensive molecular profiling evaluating for sequencing alterations (next-generation cancer sequencing panels or whole-exome sequencing or whole-genome sequencing), for copy-number analysis (single-nucleotide polymorphisms), and transcriptome profiling (RNA sequencing) be considered if clinically available, especially in relapsed and refractory patients.…”

Section: Etp Allmentioning

confidence: 99%

How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children

Teachey

O’Connor

2020

Blood

100

102

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that has historically been associated with a very poor prognosis. Nevertheless, despite a lack of incorporation of novel agents, the development of intensified T-ALL–focused protocols has resulted in significant improvements in outcome in children. Through the use of several representative cases, we highlight the key changes that have driven these advances including asparaginase intensification, the use of induction dexamethasone, and the safe omission of cranial radiotherapy. We discuss the results of recent trials to explore key topics including the implementation of risk stratification with minimal residual disease measurement and how to treat high-risk subtypes such as early T-cell precursor ALL. In particular, we address current discrepancies in treatment between different cooperative groups, including the use of nelarabine, and provide rationales for current treatment protocols for both T-ALL and T-lymphoblastic lymphoma.

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Targeting steroid resistance in T-cell acute lymphoblastic leukemia

Cited by 26 publications

References 147 publications

hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro

hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro

Gene Mutations Related to Glucocorticoid Resistance in Pediatric Acute Lymphoblastic Leukemia

How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children

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