Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15INK4b normally associated with differentiation

Martina Schmidt, Richard Koller, Peter Haviernik, Juraj Bies, Karolina Maciag, Linda Wolff

Research output: Contribution to journalArticle

Abstract

Deregulated expression of the proto-oncogene c-myb, which results from provirus integration, is thought to be responsible for transformation in a set of murine leukemia virus (MuLV)-induced myeloid leukemias (MML). We reported recently that this transcription factor promotes proliferation by directly transactivating c-myc and inhibits cell death through its up-regulation of Bcl-2 (Schmidt et al., 2000). To understand more about how these cells become transformed we looked at how they deal with cellular pathways inducing growth arrest. Specifically, we were interested in the expression of the tumor suppressor gene Cdkn2b (p15INK4b) in MML because this gene is expressed during myeloid differentiation and its inactivation by methylation has been shown to be important for the development of human acute myeloid leukemia, mRNA levels for p15INK4b and another INK4 gene p16INK4a were examined in monocytic Myb tumors and were compared with expression of the same genes in c-myc transformed monocytic tumors that do not express c-Myb. The Cdkn2a (p16INK4a) gene was generally not expressed in either tumor type, an observation explained by methylation or deletion in the promoter region. Although Cdkn2b (p15INK4b) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1. Surprisingly, in the majority of the Myb tumors there was no p15INK4b transcription and neither deletion nor methylation could explain this result. Additional experiments demonstrated that, in the presence of constitutive c-Myb expression, the induction of p15INK4b mRNA that accompanies differentiation of M1 cells to monocytes does not occur. Therefore, the transcriptional regulator c-Myb appears to prevent activation of a growth arrest pathway that normally accompanies monocyte maturation.

Original languageEnglish (US)
Pages (from-to)6205-6214
Number of pages10
JournalOncogene
Volume20
Issue number43
DOIs
StatePublished - Sep 27 2001
Externally publishedYes

Keywords

  • Myeloid leukemia
  • c-Myb
  • p15

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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