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Background  Tumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1  (SHP-1)  is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of  SHP-1  plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced  SHP-1 . Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits  FLT3  tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the  FLT3  gene ( FLT3 -ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of  SHP-1  on sensitivity to CEP-701 in resistant AML cells.    Methods  Resistant cells harboring the  FLT3 -ITD were developed by overexposure of MV4-11 to CEP-701, and the effects of 5-Aza treatment were investigated. Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays, respectively. Gene expression was performed by quantitative real-time PCR. STATs activity was examined by western blotting and the methylation profile of  SHP-1  was studied using MS-PCR and pyrosequencing analysis. Repeated-measures ANOVA and Kruskal–Wallis tests were used for statistical analysis.    Results  The cytotoxic dose of CEP-701 on resistant cells was significantly higher in comparison with parental and MV4-11R-cep + 5-Aza cells ( p  = 0.004). The resistant cells showed a significant higher viability and lower apoptosis compared with other cells ( p  < 0.001). Expression of  SHP-1  was 7-fold higher in MV4-11R-cep + 5-Aza cells compared to parental and resistant cells ( p  = 0.011). STAT3 was activated in resistant cells. Methylation of  SHP-1  was significantly decreased in MV4-11R-cep + 5-Aza cells ( p  = 0.002).    Conclusions  The restoration of  SHP-1  expression induces sensitivity towards CEP-701 and could serve as a target in the treatment of AML. Our findings support the hypothesis that, the tumor-suppressor effect of  SHP-1  is lost due to epigenetic silencing and its re-expression might play an important role in re-inducing sensitivity to TKIs. Thus,  SHP-1  is a plausible candidate for a role in the development of CEP-701 resistance in  FLT3-ITD+  AML patients.

bmc cancer

Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia