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Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Francesco Fazi
  • Serena Racanicchi
  • Giuseppe Zardo
  • Linda Marie Starnes
  • Marco Mancini
  • Lorena Travaglini
  • Daniela Diverio
  • Emanuele Ammatuna
  • Giuseppe Cimino
  • Francesco Lo-Coco
  • Francesco Grignani
  • Clara Nervi
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.
OriginalsprogEngelsk
TidsskriftCancer Cell
Vol/bind12
Udgave nummer5
Sider (fra-til)457-66
Antal sider10
ISSN1535-6108
DOI
StatusUdgivet - nov. 2007
Eksternt udgivetJa

ID: 47192932