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Zebrafish liver transcriptome in response to chronic treatment with environmentally relevant concentrations of imatinib mesylate

ABSTRACT: Imatinib mesylate (IM) a protein kinase inhibitor drug that selectively inhibits certain oncogenic mutant protein tyrosine kinases. After application, IM is via hospital and municipal waste water effluents released into the aquatic environment, where it can harm non-target organisms. The aim of this study was to evaluate changes in gene transcription in liver of adult F1 zebrafish (Danio rerio) continuously exposed to IM at environmentaly relevant concentrations of 0.01 µg/L and 1 µg/L.

ORGANISM(S): Danio rerio

PROVIDER: GSE84394 | GEO | 2019/11/05

REPOSITORIES: GEO

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Project description:The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response. Fifteen patients with confirmed CML, on IM for a minimum period of 18-months and showing suboptimal response to IM, as evidenced by failure to achieve major molecular remission (MMolR) at 18 months were identified from a series of patients treated in our centre. Patients received their medication under the auspices of the Glivec International Patient Assistance Program (GIPAP) and were started on an initial dose of 400mg with dose escalations or reductions made according to the patientM-bM-^@M-^Ys response and tolerance. Archived sequential peripheral blood lysates from the patients were retrieved and DNA/RNA extracted. Thirty-nine DNA samples of sufficient quality and quantity from the 15 patients were subjected to array-CGH analysis to identify recurrent genomic aberrations that occur through the course of disease.

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Zebrafish liver transcriptome in response to chronic treatment with environmentally relevant concentrations of imatinib mesylate

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