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

Blood. 2011 Oct 27;118(17):4666-73. doi: 10.1182/blood-2010-12-324715. Epub 2011 Aug 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anemia, Macrocytic / etiology
  • Anemia, Macrocytic / genetics*
  • Animals
  • Case-Control Studies
  • Cell Differentiation / genetics
  • Chromosome Deletion
  • Chromosomes, Human, Pair 5 / genetics
  • Erythroid Cells / metabolism
  • Erythropoiesis / genetics
  • Erythropoiesis / physiology
  • Humans
  • Loss of Heterozygosity
  • Megakaryocytes / metabolism
  • Megakaryocytes / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • MicroRNAs / physiology
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Open Reading Frames / genetics*
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • Proto-Oncogene Protein c-fli-1 / physiology
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomal Proteins / physiology
  • Tumor Cells, Cultured


  • MIRN145 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Protein c-fli-1
  • RPS14 protein, human
  • Ribosomal Proteins

Supplementary concepts

  • Chromosome 5q Deletion Syndrome