Epigenetic Silencing of the Myelopoiesis Regulator microRNA-223 by the AML1/ETO Oncoprotein

Francesco Fazi, Serena Racanicchi, Giuseppe Zardo, Linda M. Starnes, Marco Mancini, Lorena Travaglini, Daniela Diverio, Emanuele Ammatuna, Giuseppe Cimino, Francesco Lo-Coco, Francesco Grignani, Clara Nervi

Research output: Contribution to journalArticlepeer-review

Abstract

Hematopoietic transcription factors are involved in chromosomal translocations, which generate fusion proteins contributing to leukemia pathogenesis. Analysis of patient's primary leukemia blasts revealed that those carrying the t(8;21) generating AML1/ETO, the most common acute myeloid leukemia-associated fusion protein, display low levels of a microRNA-223 (miR-223), a regulator of myelopoiesis. Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. Here, we identify an additional action for a leukemia fusion protein linking the epigenetic silencing of a microRNA locus to the differentiation block of leukemia.

Original languageEnglish
Pages (from-to)457-466
Number of pages10
JournalCancer Cell
Volume12
Issue number5
DOIs
Publication statusPublished - Nov 13 2007

Keywords

  • CELLCYCLE
  • DNA

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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