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 Blood, 3 September 2009, Vol. 114, No. 10, pp. 2181-2192.
Prepublished online as a Blood First Edition Paper on July 7, 2009; DOI 10.1182/blood-2009-02-205062.

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PLATELETS AND THROMBOPOIESIS

miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53

Francisco Navarro1, David Gutman1, Eti Meire2, Mario Cáceres3, Isidore Rigoutsos4, Zvi Bentwich2, and Judy Lieberman1

1 Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA; 2 Rosetta Genomics, Rehovot, Israel; 3 Genes and Disease Program, Centre for Genomic Regulation, Barcelona, Spain; and 4 Bioinformatics and Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, NY

The role of miRNAs in regulating megakaryocyte differentiation was examined using bipotent K562 human leukemia cells. miR-34a is strongly up-regulated during phorbol ester–induced megakaryocyte differentiation, but not during hemin-induced erythrocyte differentiation. Enforced expression of miR-34a in K562 cells inhibits cell proliferation, induces cell-cycle arrest in G1 phase, and promotes megakaryocyte differentiation as measured by CD41 induction. miR-34a expression is also up-regulated during thrombopoietin-induced differentiation of CD34+ hematopoietic precursors, and its enforced expression in these cells significantly increases the number of megakaryocyte colonies. miR-34a directly regulates expression of MYB, facilitating megakaryocyte differentiation, and of CDK4 and CDK6, to inhibit the G1/S transition. However, these miR-34a target genes are down-regulated rapidly after inducing megakaryocyte differentiation before miR-34a is induced. This suggests that miR-34a is not responsible for the initial down-regulation but may contribute to maintaining their suppression later on. Previous studies have implicated miR-34a as a tumor suppressor gene whose transcription is activated by p53. However, in p53-null K562 cells, phorbol esters induce miR-34a expression independently of p53 by activating an alternative phorbol ester-responsive promoter to produce a longer pri-miR-34a transcript.


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