TY - JOUR
T1 - The involvement of microRNA in the pathogenesis of richter syndrome
AU - Roosbroeck, Katrien Van
AU - Bayraktar, Recep
AU - Calin, Steliana
AU - Bloehdorn, Johannes
AU - Dragomir, Mihnea Paul
AU - Okubo, Keishi
AU - Bertilaccio, Maria Teresa Sabrina
AU - Zupo, Simonetta
AU - You, M. James
AU - Gaidano, Gianluca
AU - Rossi, Davide
AU - Chen, Shih Shih
AU - Chiorazzi, Nicholas
AU - Thompson, Philip A.
AU - Ferrajoli, Alessandra
AU - Bertoni, Francesco
AU - Stilgenbauer, Stephan
AU - Keating, Michael J.
AU - Calin, George A.
N1 - Publisher Copyright:
© 2019 Ferrata Storti Foundation.
PY - 2019/4/30
Y1 - 2019/4/30
N2 - 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.
AB - 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.
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U2 - 10.3324/haematol.2018.203828
DO - 10.3324/haematol.2018.203828
M3 - Article
C2 - 30409799
AN - SCOPUS:85065463214
SN - 0390-6078
VL - 104
SP - 1004
EP - 1015
JO - Haematologica
JF - Haematologica
IS - 5
ER -