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Haematologica 2019 Volume 104(1):82-92
Chronic Myeloid Leukemia
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,1‡ Giulia Regazzo,1‡ Marco De Dominici,2‡ Andrea Sacconi,1 Andrea Pelosi,1† Etleva Korita,1 Francesco Marchesi,3
Francesco Pisani,3 Alessandra Magenta,4 Valentina Lulli,5 Iole Cordone,6 Andrea Mengarelli,3 Sabrina Strano,1 Giovanni Blandino,1 Maria G. Rizzo1* and Bruno Calabretta2*#
1Department of Research, Advanced Diagnostics and Technological Innovation, Oncogenomic and Epigenetic Unit, Translational Research Area, IRCCS - Regina Elena National Cancer Institute, Rome, Italy; 2Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; 3Department of Clinical and Experimental Oncology–Hematology and Stem Cell Transplant Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy; 4Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Laboratorio di Patologia Vascolare, Rome, Italy; 5Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy and 6Department of Research, Advanced Diagnostics and Technological Innovation, Clinical Pathology Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
†Present address: Department of Immunology, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy. ‡MS, GR and MDeD contributed equally to this work. #MGR and BC contributed equally as last authors.
ABSTRACT
MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many tran- scription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expres- sion 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 lym- phoblastic 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 illus- trate 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.
Introduction
The Philadelphia chromosome (Ph) is the typical chromosomal abnormality of chronic myeloid leukemia (CML) patients.1 It is also detected in a subset of B-cell acute lymphoblastic leukemia (ALL), and less frequently in acute myeloid (AML) and mixed-phenotype acute (MPAL) leukemias.1 The hallmark of the Ph chromo- some is the translocation of the proto-oncogene ABL1 from chromosome 9 to the
Correspondence:
maria.rizzo@ifo.gov.it or bruno.calabretta@jefferson.edu
Received: February 13, 2018. Accepted: July 27, 2018. Pre-published: August 3, 2018.
doi:10.3324/haematol.2018.191213
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