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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):1004-1015
Chronic Lymphocytic Leukemia
The involvement of microRNA
in the pathogenesis of Richter syndrome
Katrien Van Roosbroeck,1,2* Recep Bayraktar,1* Steliana Calin,3 Johannes Bloehdorn,4 Mihnea Paul Dragomir,1 Keishi Okubo,1 Maria Teresa Sabrina Bertilaccio,1 Simonetta Zupo,5 M. James You,3 Gianluca Gaidano,6 Davide Rossi,7 Shih-Shih Chen,8 Nicholas Chiorazzi,8 Philip A. Thompson,9 Alessandra Ferrajoli,9 Francesco Bertoni,7 Stephan Stilgenbauer,4 Michael J. Keating9 and George A. Calin1,9,10
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer
2
Center, Houston, TX, USA; Present address – Department of Investigational Cancer
Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Internal Medicine III, University Hospital Ulm, Germany; 5Molecular Diagnostic Laboratory, Pathology Department, IRCCS, Ospedale Policlinico San Martino, Genoa, Italy; 6Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; 7Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland; 8The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA; 9Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 10Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
ABSTRACT
Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independ- ent sets of patients from three institutions, we identified microRNA involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of cases of Richter syndrome. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased pro- liferation of malignant B cells in multiple assays, while miR-150 and miR- 26a were downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNA involved in both malignancy and immunity.
Introduction
The most frequent type of adult leukemia, chronic lymphocytic leukemia (CLL), is a disease in which alterations of small non-coding RNA named microRNA (miRNA, miR) play a fundamental role: the miR-15a/16-1 cluster at the 13q deletion hotspot, which targets the oncogenic anti-apoptotic proteins BCL2 and MCL1, is deleted or downregulated in most and germline-mutated in some patients.1-3 Although these discoveries were made more than a decade ago
*KVR and RB contibuted equally to this work.
Correspondence:
GEORGE A. CALIN
gcalin@mdanderson.org
Received: August 8, 2018. Accepted: November 8, 2018. Pre-published: November 8, 2018.
doi:10.3324/haematol.2018.203828
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/1004
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