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HNRNPL Restrains miR-155 Targeting of BUB1 to Stabilize Aberrant Karyotypes of Transformed Cells in Chronic Lymphocytic Leukemia

1
Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy
2
Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University Chieti-Pescara, 66100 Chieti, Italy
3
Department of Medicine and Aging Sciences, “G. d’Annunzio” University Chieti-Pescara, 66100 Chieti, Italy
4
Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
5
Institute of Hematology, Catholic University of the Sacred Heart, 00168 Rome, Italy
6
Department of Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA
7
Chronic Lymphocytic Leukemia Research Consortium, San Diego, CA 92093, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(4), 575; https://doi.org/10.3390/cancers11040575
Received: 20 March 2019 / Revised: 15 April 2019 / Accepted: 19 April 2019 / Published: 23 April 2019
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Abstract

Aneuploidy and overexpression of hsa-miR-155-5p (miR-155) characterize most solid and hematological malignancies. We recently demonstrated that miR-155 sustains aneuploidy at early stages of in vitro cellular transformation. During in vitro transformation of normal human fibroblast, upregulation of miR-155 downregulates spindle checkpoint proteins as the mitotic checkpoint serine/threonine kinase budding uninhibited by benzimidazoles 1 (BUB1), the centromere protein F (CENPF) and the zw10 kinetochore protein (ZW10), compromising the chromosome alignment at the metaphase plate and leading to aneuploidy in daughter cells. Here we show that the heterogeneous nuclear ribonucleoprotein L (HNRNPL) binds to the polymorphic marker D2S1888 at the 3′UTR of BUB1 gene, impairs the miR-155 targeting, and restores BUB1 expression in chronic lymphocytic leukemia. This mechanism occurs at advanced passages of cell transformation and allows the expansion of more favorable clones. Our findings have revealed, at least in part, the molecular mechanisms behind the chromosomal stabilization of cell lines and the concept that, to survive, tumor cells cannot continuously change their genetic heritage but need to stabilize the most suitable karyotype. View Full-Text
Keywords: miR-155; BUB1; HNRNPL; CIN; CLL and microRNA miR-155; BUB1; HNRNPL; CIN; CLL and microRNA
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Pagotto, S.; Veronese, A.; Soranno, A.; Balatti, V.; Ramassone, A.; Guanciali-Franchi, P.E.; Palka, G.; Innocenti, I.; Autore, F.; Rassenti, L.Z.; Kipps, T.J.; Mariani-Costantini, R.; Laurenti, L.; Croce, C.M.; Visone, R. HNRNPL Restrains miR-155 Targeting of BUB1 to Stabilize Aberrant Karyotypes of Transformed Cells in Chronic Lymphocytic Leukemia. Cancers 2019, 11, 575.

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