Coordinate Loss of a MicroRNA Mir 145 and a Protein-Coding Gene RPS14 Cooperate in the Pathogenesis of 5q- Syndrome.

Abstract 947

Large hemizygous chromosomal deletions are among the most common molecular abnormalities in cancer, but the identification of critical haploinsufficiency disease genes within the deleted regions has been difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a well-studied chromosomal deletion syndrome characterized by a consistent clinical phenotype with macrocytic anemia and thrombocytosis. We have previously shown that while hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not account for the thrombocytosis. Evaluation of the effects of all protein coding genes in the CDR on hematopoietic differentiation showed no genes other than RPS14 altered the ratio of megakaryocytic to erythroid cells, either alone or in combination with RPS14. We therefore examined the 5q- syndrome CDR for non-coding RNAs and identified a microRNA, miR-145, which targets Fli-1, a transcriptional factor that regulates megakaryocyte development. 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 in CD34+ cells decreases megakaryocyte production, while inhibition of miR-145 or overexpression of Fli-1 has the reciprocal effect. These findings have been validated in vivo using transgenic mice. Moreover, the combined loss of miR-145 and RPS14 cooperate to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate for the first time that coordinate deletion of a microRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.