Down-regulation of Notch-1 expression decreases PU.1-mediated myeloid differentiation signaling in acute myeloid leukemia

Po Min Chen, Chueh Chuan Yen, Wei Shu Wang, Yu Jen Lin, Chiau Jun Chu, Tzeon Jye Chiou, Jin Hwang Liu, Muh Hwa Yang

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

The Notch receptor-mediated signaling pathways control cell fate in many types of organisms including neurogenesis, myogenesis and hematopoiesis in mammalian species. During normal hematopoiesis, Notch-1 promotes myeloid differentiation through up-regulation of the transcriptional factor PU.1. We therefore speculated that down-regulation of Notch-1 expression might be involved in the leukemogenesis of acute myeloid leukemia (AML). Here we investigated Notch-1 expression and its association with PU.1-mediated differentiation signaling in AML. The transcriptional level of Notch-1 and PU.1 was evaluated in 6 AML cell lines and 54 AML patient samples using real-time PCR analysis, and Western blot analysis of Notch-1, PU.1 and one of its downstream targets, the M-CSF receptor (MCSFR), was performed to test for confirmation. A significant decrease in the transcription levels of Notch-1 was noted in AML cell lines and patient samples, and decreased Notch-1 protein expression in AML was confirmed by Western blotting. Down-regulation of Notch-1 expression was associated with a decrease in PU.1/MCSFR expression in AML. Co-immunoprecipitation experiments showed that partial disruption of the Notch-1/PU.1 complex was noted in AML cells. No detectable mutation of Notch-1 (ANK, PEST) and PU.1 (PEST, DBD) was noted by PCR-single-strand conformation polymorphism (SSCP) assay. These results suggest that down-regulation of Notch-1 expression decreases PU.1/MCSFR expression and disrupts the Notch-1/PU.1 complex, which may impede the PU.l-mediated myeloid signaling and contribute to the leukemogenesis of AML.

Original languageEnglish
Pages (from-to)1335-1341
Number of pages7
JournalInternational Journal of Oncology
Volume32
Issue number6
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Differentiation
  • Notch-1
  • PU.1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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