Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells

Manuela Spagnuolo, Giulia Regazzo, Marco De Dominici, Andrea Sacconi, Andrea Pelosi, Etleva Korita, Francesco Marchesi, Francesco Pisani, Alessandra Magenta, Valentina Lulli, Iole Cordone, Andrea Mengarelli, Sabrina Strano, Giovanni Blandino, Maria G. Rizzo, Bruno Calabretta

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Abstract

MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expression in Philadelphia-positive (Ph+) leukemia cells and if MYB-regulated microRNAs are important for the “MYB addiction” of these cells. Thirty-five microRNAs were modulated by MYB silencing in lymphoid and erythro-myeloid chronic myeloid leukemia-blast crisis BV173 and K562 cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/β-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from 2 Ph+ leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph+ acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/β-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph+ cells and supports the concept that the “MYB addiction” of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival.

Original languageEnglish
Pages (from-to)82-92
Number of pages11
JournalHaematologica
Volume104
Issue number1
DOIs
Publication statusE-pub ahead of print - Aug 3 2018

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ASJC Scopus subject areas

  • Hematology

Cite this

Spagnuolo, M., Regazzo, G., De Dominici, M., Sacconi, A., Pelosi, A., Korita, E., Marchesi, F., Pisani, F., Magenta, A., Lulli, V., Cordone, I., Mengarelli, A., Strano, S., Blandino, G., Rizzo, M. G., & Calabretta, B. (2018). Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells. Haematologica, 104(1), 82-92. https://doi.org/10.3324/haematol.2018.191213