The involvement of microRNA in the pathogenesis of Richter syndrome
Katrien Van Roosbroeck,
Recep Bayraktar,
Steliana Calin,
Johannes Bloehdorn,
Mihnea Paul Dragomir,
Keishi Okubo,
Maria Teresa Sabrina Bertilaccio,
Simonetta Zupo,
M. James You,
Gianluca Gaidano,
Davide Rossi,
Shih-Shih Chen,
Nicholas Chiorazzi,
Philip A. Thompson,
Alessandra Ferrajoli,
Francesco Bertoni,
Stephan Stilgenbauer,
Michael J. Keating,
George A. Calin
Affiliations
Katrien Van Roosbroeck
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Present address – Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Recep Bayraktar
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Steliana Calin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Johannes Bloehdorn
Department of Internal Medicine III, University Hospital Ulm, Germany
Mihnea Paul Dragomir
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Keishi Okubo
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Maria Teresa Sabrina Bertilaccio
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Davide Rossi
Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland
Shih-Shih Chen
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
Nicholas Chiorazzi
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
Philip A. Thompson
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Alessandra Ferrajoli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Francesco Bertoni
Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland
Stephan Stilgenbauer
Department of Internal Medicine III, University Hospital Ulm, Germany
Michael J. Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
George A. Calin
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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 independent 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 proliferation 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.
