Details

Autor(en) / Beteiligte

• FORREST, Arr
• KANAMORI-KATAYAMA, M
• YASUDA, J
• KAWAI, J
• HAYASHIZAKI, Y
• HUME, D. A
• SUZUKI, H
• TOMARU, Y
• LASSMANN, T
• NINOMIYA, N
• TAKAHASHI, Y
• DE HOON, Mjl
• KUBOSAKI, A
• KAIHO, A
• SUZUKI, M

Titel

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Ist Teil von

• Leukemia, 2010-02, Vol.24 (2), p.460-466

Ort / Verlag

Avenel, NJ: Nature Publishing Group

Erscheinungsjahr

2010

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced microRNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these pro-differentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.