Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation

Griffiths, Elizabeth A.; Gore, Steven D.; Hooker, Craig M.; McDevitt, Michael A.; Karp, Judith E.; Smith, B. Douglas; Mohammad, Helai P.; Ye, Ying; Herman, James G.; Carraway, Hetty E.

doi:10.3109/10428194.2010.496505

Cited by 72 publications

(81 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, APC2 methylation is rarely observed in epithelial tumors (6). The results of the present study demonstrated that APC2 promoter methylation remained unchanged by various chemotherapy treatments.…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

Xia

Hong

Chen

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Aberrant promoter DNA methylation is a major mechanism of leukemogenesis in hematologic malignancies, including acute myeloid leukemia (AML). However, the association between promoter methylation with chemotherapeutic outcomes remains unknown. In the present study, bone marrow samples were collected prior to and following chemotherapy in 30 AML patients. Methylation-specific polymerase chain reaction technology was used to examine the promoter methylation status of adenomatous polyposis col 2 (APC2) and cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1). The results revealed no change in the methylation status of the APC2 promoter in patients following various chemotherapy regimens. However, the methylation status of the CYP1B1 promoter changed in response to 6 different chemotherapy regimens. AML patients of the M3 subtype displayed an induction of the CYP1B1 promoter methylation levels more frequently (57.1%) than patients affected by the other subtypes (M1: 33.3%; M2: 12.5%; M4: 16.7%; M5: 0% and M6: 0%). In addition, a higher frequency of male patients (4/13) exhibited modulation of the CYP1B1 promoter methylation status compared with female patients (3/17). Furthermore, of five AML patients with a poor prognosis, two exhibited changes leading to CYP1B1 hypomethylation and two leading to CYP1B1 hypermethylation. By contrast, three other patients exhibited hypermethylation changes along with remission. This may be explained by the different chemotherapy regimens used to treat these patients or by other unknown factors. The present study revealed that CYP1B1 promoter methylation was induced during chemotherapy, whereas the APC2 promoter remained hemimethylated. Furthermore, the changes in CYP1B1 methylation were dependent on the AML subtypes and the gender of the patients. IntroductionPromoter methylation is important in epigenetics and always leads to transcriptional silencing of tumor suppressor genes in acute myeloid leukemia (AML) (1). Although current chemotherapy regimens result in complete remission in many cases, there is no standard and efficient therapy for refractory AML (2). As aberrant DNA methylation is common in AML, clinical trials using epigenetically-targeted therapies have yielded particularly promising results in the treatment of hematopoietic malignancies (3). Several demethylating agents, including azacytidine and decitabine, have been demonstrated to improve AML prognosis (4).Adenomatous polyposis col 2 (APC2) is a tumor suppressor gene, encoding a protein that controls the stability and nuclear export of β-catenin, which is a Wnt signaling pathway transcriptional coactivator (5). Wnt pathway inhibitors are methylated at a high frequency in AML patients (6). The cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1) gene, which is a candidate target gene in numerous types of cancers, encodes a member of the cytochrome P450 enzyme superfamily. Furthermore, cytochrome P450 enzymes are involved in drug metabolism and the synthesis of cholesterol, steroids and other l...

show abstract

Section: Discussionsupporting

confidence: 52%

“…Wnt pathway inhibitors are methylated at a high frequency in AML patients (6). The cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1) gene, which is a candidate target gene in numerous types of cancers, encodes a member of the cytochrome P450 enzyme superfamily.…”

Section: Introductionmentioning

confidence: 99%

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

Xia

Hong

Chen

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…t(8;21)(q22;q22) is the most frequent karyotypic abnormality in AML, which is characterized by the clonal proliferation of haematopoietic stem or progenitor cells [127,128]. In AML, abnormal nuclear localization of non-phosphorylated β-catenin has been demonstrated both in vitro and in patient samples [125,129].…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

Secreted frizzled related proteins: Implications in cancers

Surana

Sikka

Cai

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

103

114

View full text Add to dashboard Cite

show abstract

“…Aberrant activation of the Wingless-type MMTV integration site family (WNT)/β-catenin pathway has been implicated in the pathogenesis of many malignancies (1)(2)(3). The phenomenon has also been observed in hematological malignancies (4,5).…”

Section: Introductionmentioning

confidence: 94%

“…Abnormal methylation of WNT antagonists is a frequent event in several human malignancies (7,24,25). Previous studies have indicated that methylation of SFRP exists in leukemia (1,2). Our previous studies demonstrated that inhibitory factors of the WNT pathway, such as WNT inhibitory factor, DKK1 and SFRP1, are hypermethylated in leukemia cells and patients with leukemia (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide increases expression of secreted frizzled-related protein 1 gene and inhibits the WNT/β-catenin signaling pathway in Jurkat cells

Wang

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. The aim of the present study was to investigate the demethylation effect of arsenic trioxide (As 2 O 3 ) on the secreted frizzled-related protein 1 (SFRP1) gene and its ability to inhibit the Wingless-type MMTV integration site family (WNT) pathway in Jurkat cells. Methylation-specific polymerase chain reaction was used to examine the CpG island methylation status of the SFRP1 gene in leukemia cell lines. In addition, the effects on Jurkat cells of treatment with different concentrations of As 2 O 3 for 48 h were investigated. Reverse transcription-quantitative polymerase chain reaction was employed to measure the expression of mRNAs, while western blot analysis was used to examine protein expression in cells. The SFRP1 gene was methylated in Jurkat cells. However, both methylated and unmethylated SFRP1 genes were detected in HL60 and K562 cells. In normal bone marrow mononuclear cells, the SFRP1 gene was unmethylated. Following treatment with As 2 O 3 for 48 h, the SFRP1 gene was demethylated, and the mRNA and protein expression levels of the SFRP1 gene were increased. By contrast, the mRNA and protein expression levels of β-catenin and cyclin Dl were downregulated. The protein expression of c-myc was also downregulated, but As 2 O 3 exhibited no significant effect on the mRNA expression of c-myc. Abnormal methylation of the SFRP1 gene was detected in Jurkat cells. These results suggest that As 2 O 3 activates SFRP1 gene expression at the mRNA and protein levels in Jurkat cells by demethylation of the SFRP1 gene. Furthermore, they indicate that As 2 O 3 regulates WNT target genes and controls the growth of Jurkat cells through the WNT/β-catenin signaling pathway.

show abstract

Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation

Cited by 72 publications

References 37 publications

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

APC2 and CYP1B1 methylation changes in the bone marrow of acute myeloid leukemia patients during chemotherapy

Secreted frizzled related proteins: Implications in cancers

Arsenic trioxide increases expression of secreted frizzled-related protein 1 gene and inhibits the WNT/β-catenin signaling pathway in Jurkat cells

Contact Info

Product

Resources

About