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.
Epigenetic silencing of the myelopoiesis-regulator microRNA-223 by the AML1/ETO oncoprotein / Fazi, Francesco; Racanicchi, S; Zardo, Giuseppe; Starnes, Lm; Mancini, M; Travaglini, L; Diverio, D; Ammatuna, E; Cimino, Giuseppe; LO COCO, F; Grignani, F; Nervi, Clara. - In: CANCER CELL. - ISSN 1535-6108. - STAMPA. - 12:(2007), pp. 457-466. [10.1016/j.ccr.2007.09.020]
Epigenetic silencing of the myelopoiesis-regulator microRNA-223 by the AML1/ETO oncoprotein
FAZI, Francesco;ZARDO, GIUSEPPE;CIMINO, Giuseppe;NERVI, Clara
2007
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.