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Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

ABSTRACT: Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.

SUBMITTER: Kumar MS

PROVIDER: S-EPMC3208282 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

Kumar Madhu S MS Narla Anupama A Nonami Atsushi A Mullally Ann A Dimitrova Nadya N Ball Brian B McAuley J Randall JR Poveromo Luke L Kutok Jeffrey L JL Galili Naomi N Raza Azra A Attar Eyal E Gilliland D Gary DG Jacks Tyler T Ebert Benjamin L BL

Blood 20110826 17

Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA locat ...[more]

PMID: 21873545

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Dataset Information

Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

Publications

Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

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