The mechanism of action of the negative Regulators of jak/stat singnaling pathway in Resistant FLT-ITD acute myeloid leukaemia cells

Johan, Muhammad Farid (2019) The mechanism of action of the negative Regulators of jak/stat singnaling pathway in Resistant FLT-ITD acute myeloid leukaemia cells. The mechanism of action of the negative Regulators of jak/stat singnaling pathway in Resistant FLT-ITD acute myeloid leukaemia cells.

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Abstract

The aim of this study was to understand the mechanism of action of negative regulators of JAK/STAT signalling pathway in FLT3-ITD AML cell lines with different response towards the FLT3 inhibitors PKC412 and CEP701. The cytotoxic dose of CEP-701 and PKC-412 on resistant cell lines was significantly higher in comparison with parental and MV4-11 R-cep+5-Aza (p=0.004) and MV4-11pkc+5-Aza (p=0.003). The resistant cells showed a significant higher viability and lower apoptosis compared with others (p<0.001 ). Expression of SHP-1 and PRG2 were 7 and 20- folds higher in MV4-11R-cep+5-Aza compared to parental and resistant (p=0.011). There was significant hypomethylation (p=0.002) in CpG islands of SHP-1 and PRG2, associated with their re-expressions. The higher sensitivity to TKI was associated with STAT3 inactivation in 5-Aza treated compared with their resistant cell lines. 20-PAGE showed the number of protein spots detected were 522±29 with 79% matching rate which resulted in three upregulated proteins. The restoration of SHP-1 and PRG2 expression induces sensitivity towards CEP-701. 5-Aza enhances efficacy of TKI and treatment with 5-Aza followed by PKC-412 or CEP-701 could provide suitable candidates for further investigates to underline alternative options for the treatment of AML patients with FL T3-ITD.

Item Type: Article
Uncontrolled Keywords: leukaemia
Subjects: R Medicine
Divisions: Kampus Kesihatan (Health Campus) > Pusat Pengajian Sains Perubatan (School of Medical Sciences) > Article
Depositing User: Mr Abdul Hadi Mohammad
Date Deposited: 27 Feb 2022 03:44
Last Modified: 27 Feb 2022 03:44
URI: http://eprints.usm.my/id/eprint/51676

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