期刊
HAEMATOLOGICA
卷 104, 期 5, 页码 1004-1015出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.203828
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资金
- National Institutes of Health (NIH/NCATS) through the NIH Common Fund, Office of Strategic Coordination (OSC), National Cancer Institute (NCI) [UH3TR00943-01, 1R01 CA182905-01, 1R01CA222007-01A1]
- NIGMS [1R01GM122775-01]
- U54 grant - UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project
- Team DOD grant [CA160445P1]
- Ladies Leukemia League grant
- Lauri Strauss Leukemia Foundation
- POC grant [35/01.09.2016, 37_796]
- Helmut Horten Foundation
- San Salvatore Foundation
- Oncosuisse [OCS-02296-082008]
- DFG [SFB1074]
- NIH/NCI [R01 CA164346]
- IRG of the University of Texas MD Anderson Cancer Center
- AIRC 5 x 1000 project, AIRC, Milan, Italy [21198]
- Italian Ministry of Health
- SINF 2017 grant
- Estate of C. G. Johnson
- CLL Moonshot Flagship project
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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