Epigenetic Inactivation of Notch-Hes Pathway in Human B-Cell Acute Lymphoblastic Leukemia

نویسندگان

  • Shao-Qing Kuang
  • Zhihong Fang
  • Patrick A. Zweidler-McKay
  • Hui Yang
  • Yue Wei
  • Emilio A. Gonzalez-Cervantes
  • Yanis Boumber
  • Guillermo Garcia-Manero
چکیده

The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Investigating the inhibitory effect of miR-34a, miR-449a, miR-1827, and miR-106b on target genes including NOTCH1, c-Myc, and CCND1 in human T cell acute lymphoblastic leukemia clinical samples and cell line

Objective(s): microRNAs are small non-coding molecules that regulate gene expression in various biological processes. T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy accompanied with genetic aberrations and accounts for 20% of children’s and adult’s ALL. Notch signaling pathway dysregulation occurs in 60% of T-ALL cases. In the present study, we aimed to de...

متن کامل

Epigenetic effects of decitabine on acute lymphoblastic and acute promyelocytic leukemia cells

Background: Decitabine (5-aza-2'-deoxycytidine, DAC) is a deoxycytidine analog currently used as an effective drug against myelodysplastic syndromes and acute myeloid leukemia. Although various studies have pointed out the epigenetic effects of this drug, its epigenetic mechanisms in different leukemic cell lines are not specified. In this lab trial study, possible epigenetic effects of decitab...

متن کامل

اثر سینرژیستی ایندول تری کربینول با دوکسوروبیسین در افزایش القای آپوپتوز بر رده سلولی لوسمی لنفوبلاستیک حاد (NALM-6)

Background and Aim: Indole-3-carbinol (I3C), found in Brassica species vegetables, exhibits antitumor effects. It has been shown that I3C induces apoptosis in various cell types through inactivation of the nuclear factor-kappa B (NF- k B) pathway. Anthracyclines such as doxorubicin, is widely used in the treatment of hematological malignancies, induce apoptosis in tumor cells via DNA damage and...

متن کامل

MicroRNAs as a New Molecular Biomarker for Diagnosis and Prognosis of T-cell Acute Lymphoblastic Leukemia (T-ALL): A Systematic Review

MicroRNAs (miRNAs, miRs) are small endogenous non-coding RNAs that regulate the expression of protein-encoding genes at the post-transcriptional level. Several studies have described the role of miRNAs in T-cell acute lymphoblastic leukemia (T-ALL), including tumor suppressor and oncogenic miRNAs. Down-regulation of miRNA expression is a prominent feature of human malignancy. This down-regulati...

متن کامل

A Comparison between the Anticancer Activities of Free Paclitaxel and Paclitaxel-Loaded Niosome Nanoparticles on Human Acute Lymphoblastic Leukemia Cell Line Nalm-6

Background: Niosomes or Nonionic surfactant vesicles are nano vehicles utilized in drug delivery systems, especially in cancer therapy. In this study, these vesicles were applied as delivery system for anticancer drug, paclitaxel and then, its anticancer activities was compared with free paclitaxel on Human Acute Lymphoblastic Leukemia (ALL) cell line Nalm-6. Materialas and Methods: In this exp...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2013