The involvement of microRNA in the pathogenesis of Richter syndrome

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 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.

miRNAs in the Diagnosis and Prognosis of Skin Cancer

“…This technology was used for detecting miRNAs in brain diseases (Hoss et al, 2015), in brain metastases of breast cancer (Le et al, 2014), or, more recently, in Richter syndrome, the syndrome that shows the switch of chronic lymphocytic leukemia into its aggressive form (Van Roosbroeck et al, 2019). Unfortunately, although this technology has good potential, reports using this assay in skin cancer are not yet published.…”

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

“…The deleted in lymphocytic leukemia 1 lncRNA (DLEU1) was discovered due to its location on chromosome 13q14.3, a region which is commonly deleted in chronic B-cell lymphocytic leukemia [103][104][105]. Beside DLEU1, this locus also hosts miR-15a and miR-16 which are the first ever discovered ncRNAs to be involved in human diseases [106][107][108][109]. Though in hematopoietic tumors DLEU1 can act as a potential tumor suppressor [110], in other cancers including cervical cancer [111], colorectal cancer [112], and NSCLC [113] it has been shown to exert oncogenic function.…”

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

“…Epstein-Barr virus (EBV)-miRNAs are also involved in regulating the surrounding microenvironment of the infected B-malignant cells. EBV is a member of the human gamma-herpesvirus family that is involved in human malignancies, including several types of lymphomas [84,85]. MiRNAs encoded by EBV are believed to be involved in the EBV-induced lymphomagenesis.…”

“…These miRNAs contribute to the pathogenic effects of EBV through directly targeting cellular and/or viral mRNAs and thus interfering with several important cellular mechanisms, such as survival, proliferation, immune escape, and apoptosis. Moreover, EBV-miRNAs can regulate the surrounding microenvironment of the infected lymphoma cells with strong implications in cancer immunosurveillance [84][85][86][87]. For instance, in EBV-associated NHLs, the increased levels of BHRF1-3 were inversely correlated with the expression of its direct cellular chemokine target CXCL-11/I-TAC [88].…”