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

Madhu S. Kumar, Anupama Narla, Atsushi Nonami, Ann Mullally, Nadya Dimitrova, Brian Ball, J. Randall McAuley, Luke Poveromo, Jeffrey L. Kutok, Naomi Galili, Azra Raza, Eyal Attar, D. Gary Gilliland, Tyler Jacks, Benjamin L. Ebert

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64 Citations (Scopus)

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 miRNAand a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.

Original languageEnglish
Pages (from-to)4666-4673
Number of pages8
JournalBlood
Volume118
Issue number17
DOIs
Publication statusPublished - Oct 27 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kumar, M. S., Narla, A., Nonami, A., Mullally, A., Dimitrova, N., Ball, B., McAuley, J. R., Poveromo, L., Kutok, J. L., Galili, N., Raza, A., Attar, E., Gilliland, D. G., Jacks, T., & Ebert, B. L. (2011). Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood, 118(17), 4666-4673. https://doi.org/10.1182/blood-2010-12-324715