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HSH2D contributes to methotrexate resistance in human T?cell acute lymphoblastic leukaemia.

ABSTRACT: Acute lymphoblastic leukaemia (ALL) is a malignant proliferative disease that originates from B?lineage or T?lineage lymphoid progenitor cells. Resistance to chemotherapy remains an important factor for treatment failure. The aim of the present study was to investigate drug resistance in T?cell ALL (T?ALL). Bioinformatics analysis of Oncomine and Gene Expression Omnibus data was performed to evaluate the expression of haematopoietic SH2 domain containing (HSH2D) in various lymphomas. HuT?78 cells with HSH2D overexpression and or knockdown were constructed, and the effect on related downstream signalling molecules was detected. To study the effect of HSH2D on methotrexate (MTX) resistance, cell cycle and apoptosis analyses were conducted using flow cytometry, and MTT and EdU assays were used to detect the effect of MTX resistance and HSH2D gene expression on the biological function of HuT?78 cells. Via the analysis of the data sets, it was identified that the expression of HSH2D was downregulated in T?ALL compared with B?cell ALL. Western blotting and reverse transcription?quantitative PCR demonstrated that the overexpression of HSH2 resulted in the inhibition of CD28?mediated IL?2 activation. In related experiments with drug?resistant cell lines, it was determined that HSH2D expression is necessary for HuT?78 cells to be resistant to MTX. In conclusion, the results suggested that HSH2D serves an important role in the resistance of T?ALL to MTX, which provides a potential research target for the study of drug resistance of T?ALL.

SUBMITTER: Wang J

PROVIDER: S-EPMC7551555 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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HSH2D contributes to methotrexate resistance in human T‑cell acute lymphoblastic leukaemia.

Wang Jing J Xiong Yiying Y

Oncology reports 20200917 5

Acute lymphoblastic leukaemia (ALL) is a malignant proliferative disease that originates from B‑lineage or T‑lineage lymphoid progenitor cells. Resistance to chemotherapy remains an important factor for treatment failure. The aim of the present study was to investigate drug resistance in T‑cell ALL (T‑ALL). Bioinformatics analysis of Oncomine and Gene Expression Omnibus data was performed to evaluate the expression of haematopoietic SH2 domain containing (HSH2D) in various lymphomas. HuT‑78 cell ...[more]

PMID: 33000278

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Project description:IntroductionMethotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use.MethodsTo better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX.ResultsMTX altered the concentration of 31 out of 70 metabolites analyzed, suggesting inhibition of the glycine cleavage system, the pentose phosphate pathway, purine and pyrimidine synthesis, phospholipid metabolism, and bile acid uptake. We found that glutathione (GSH) levels were associated with MTX resistance in both treated and untreated cells, suggesting a new constitutive metabolic-based mechanism of resistance to the drug. Gene expression analyses showed that eight genes involved in GSH metabolism were correlated to GSH concentrations, 2 of which (gamma-glutamyltransferase 1 [GGT1] and thioredoxin reductase 3 [TXNRD3]) were also correlated to MTX resistance. Gene set enrichment analysis (GSEA) confirmed the association between GSH metabolism and MTX resistance. Pharmacological inhibition or stimulation of the main antioxidant systems of the cell, GSH and thioredoxin, confirmed their importance in MTX resistance. Arsenic trioxide (ATO), a thioredoxin inhibitor used against acute promyelocytic leukemia, potentiated MTX cytotoxicity in vitro in some of the ALL cell lines tested. Likewise, the ATO+MTX combination decreased tumor burden and extended the survival of NOD scid gamma (NSG) mice transplanted with patient-derived ALL xenograft, but only in one of four ALLs tested.ConclusionAltogether, our results show that the cellular antioxidant defense systems contribute to leukemia resistance to MTX, and targeting these pathways, especially the thioredoxin antioxidant system, may be a promising strategy for resensitizing ALL to MTX.

Project description:BackgroundAbout a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome.MethodsLeukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL.Findings30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial).InterpretationETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy.FundingUS National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).

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HSH2D contributes to methotrexate resistance in human T?cell acute lymphoblastic leukaemia.

Publications

HSH2D contributes to methotrexate resistance in human T‑cell acute lymphoblastic leukaemia.

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