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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Date
2019
Authors
Johan, Muhammad Farid
Journal Title
Journal ISSN
Volume Title
Publisher
Pusat Pengajian Sains Perubatan, Universiti Sains Malaysia
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.
Description
Keywords
leukaemia