Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein.
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.
Fazi
Francesco
F
Department of Histology and Medical Embryology, University La Sapienza, Rome, 00161, Italy.
Racanicchi
Serena
S
Zardo
Giuseppe
G
Starnes
Linda M
LM
Mancini
Marco
M
Travaglini
Lorena
L
Diverio
Daniela
D
Ammatuna
Emanuele
E
Cimino
Giuseppe
G
Lo-Coco
Francesco
F
Grignani
Francesco
F
Nervi
Clara
C
D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D018922:HL-60 Cells; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D038042:Myelopoiesis; D015513:Oncogene Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C525067:MIR223, human; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human