Expression of Pten and Shp1, Investigated From Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia

Gauffin, Fredrika; Diffner, Eva; Gustafsson, Bertil; Nordgren, Ann; Wingren, Anette Gjörloff; Sander, Birgitta; Persson, Jenny L.; Gustafsson, Britt

doi:10.1080/08880010802625530

Cited by 16 publications

(9 citation statements)

References 20 publications

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“…These findings suggest that, the up-regulated DNMTs in the parental and resistant cells methylate the CpG islands of SHP-1 and PRG2 genes, resulting in their transcriptional silencing. Our findings are consistent with previous reports that revealed hypermethylation of SHP-1 and PRG2 in leukemic cell lines [ 22 , 38 , 42 , 49 ].…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2015

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BackgroundTumor-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.MethodsResistant 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.ResultsThe 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).ConclusionsThe 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.

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Section: Discussionsupporting

confidence: 94%

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

et al. 2015

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“…Our results showed that DNA methylation of SOCS1 gene was a protective factor for leukemia. SHP1 is tumor suppressor gene involved in the regulation of cell cycle control and apoptosis [29]. SHP1 is negative regulator of the Jak/STAT signaling pathway that is implicated in leukemogenesis.…”

Section: Discussionmentioning

confidence: 99%

The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

et al. 2014

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BackgroundAccumulating evidence supports a role of DNA methylation in the pathogenesis of leukemia. The aim of our study was to evaluate the potential genes with aberrant DNA methylation in the prediction of leukemia risk by a comprehensive meta-analysis of the published data.MethodsA series of meta-analyses were done among the eligible studies that were harvested after a careful filtration of the searching results from PubMed literature database. Mantel-Haenszel odds ratios and 95% confidence intervals were computed for each methylation event assuming the appropriate model.ResultsA total of 535 publications were initially retrieved from PubMed literature database. After a three-step filtration, we harvested 41 case-control articles that studied the role of gene methylation in the prediction of leukemia risk. Among the involving 30 genes, 20 genes were shown to be aberrantly methylated in the leukemia patients. A further subgroup meta-analysis by subtype of leukemia showed that CDKN2A, CDKN2B, ID4 genes were significantly hypermethylated in acute myeloid leukemia.ConclusionsOur meta-analyses identified strong associations between a number of genes with aberrant DNA methylation and leukemia. Further studies should be required to confirm the results in the future.

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“…Low expression of SHP1 in normal epithelial cells contrasts with dramatically upregulated SHP1 expression in several human tumors including epithelial breast and ovarian tumors (20,23,24) suggesting a potential role for SHP1 in modulation of tumor cell proliferation. The molecular mechanisms underlying the upregulated expression of SHP1 in epithelial tumors have not been determined.…”

Section: Introductionmentioning

confidence: 94%

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Amin

Kumar

Nilchi

et al. 2011

Molecular Cancer Research

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In this study, we show that proliferation of breast cancer cells is suppressed by IGF-1-activated JNK MAPK pathway. The molecular mechanism by which c-jun-NH,-kinase (JNK) activation induces antiproliferative signals in IGF-1-stimulated breast cancer cells remains unknown. Tyrosine phosphatase SHP1 is known to negatively regulate signal transduction pathways activated by cell surface receptors including IGF-1. Moreover, SHP1 transcript and protein levels are increased in epithelial tumors. Therefore, we hypothesized that IGF-activated JNK induces expression of SHP1 in breast cancer cells. To further clarify the role of SHP1 in tumor growth, we correlated the proliferation rates of breast adenocarcinoma cells with SHP1 expression and JNK activation. We show that proliferation of serum-or IGF-1-stimulated breast adenocarcinoma cells is negatively regulated by SHP1 and show for the first time that IGF-1-activated JNK induces SHP1 expression in MCF-7 cells used as experimental model. In an attempt to understand the mechanism by which serum-or IGF-1-activated JNK induces SHP1 expression resulting in suppression of cell proliferation, we reveal for the first time that in serum-or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. Overall, we show for the first time that IGF-1-stimulated proliferation of breast adenocarcinoma cells is negatively regulated by SHP1 through activation of JNK. Mol Cancer Res; 9(8); 1112-25. Ó2011 AACR.

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Expression of Pten and Shp1, Investigated From Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia

Cited by 16 publications

References 20 publications

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

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

The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

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