c-Myc overcomes cell cycle inhibition by CBFβ-SMMHC, a myeloid leukemia oncoprotein

Florence Bernardin, Yandan Yang, Curt I. Civin, Alan D. Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

Thirty percent of acute myeloid leukemia cases express a Core Binding Factor (CBF) oncoprotein or harbor point mutations in one or both AML1 (RUNX1) genes. Each of these alterations reduces endogenous CBF activities. CBFβ-SMMHC is expressed from the inv(16) chromosome in 8% of AML cases and inhibits endogenous CBF DNA-binding. Inhibition of CBF reduces Retinoblastoma protein phosphorylation and slows the G1 to S cell cycle transition. c-Myc, a protein which stimulates S phase entry, is over-expressed in one-third of AMLs. We have developed Ba/F3 cell lines in which zinc regulates CBFβ-SMMHC expression and 4-hydroxytamoxifen activates c-Myc-ER. In these lines, c-Myc-ER overcomes inhibition of cell cycle progression mediated by CBFβ-SMMHC. CBFβ-SMMHC does not affect endogenous c-Myc RNA levels, indicating that CBF does not regulate the c-Myc gene. Conversely, c-Myc-ER does not alter CBF DNA-binding activity. Thus, c-Myc-ER acts downstream of CBFβ-SMMHC to stimulate cell cycle progression. In a subset of CBF leukemias, elevated expression of c-Myc is expected to facilitate the proliferation of the leukemic blasts and thereby potentiate the ability of CBF oncoproteins to block differentiation.

Original languageEnglish (US)
Pages (from-to)492-496
Number of pages5
JournalCancer Biology and Therapy
Volume1
Issue number5
DOIs
StatePublished - Sep 2002

Keywords

  • AML1
  • CBF
  • CBFβ-SMMHC
  • RUNX1
  • c-Myc

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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