Sonali Sharma and her colleagues from Marek Mraz laboratory have shown that a short RNA molecule called miR-29 coordinates the activation of a pathway essential for cell proliferation and aggressiveness in B-cell leukaemia. CD40 signalling or T-cell interaction is one of the critical factors for the proliferation of malignant B-cells. This study provides a better understanding of the regulation of this pathway and could help in improving the current therapeutic approaches in chronic lymphocytic leukaemia or other B-cell malignancies. The research findings open up the possibility to use microRNAs as therapeutic targets and explain why drugs that block BCR signalling also block the B – T cell interactions. This study was published in the scientific journal Blood (IF 23,6).

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in regulating the gene expression. Chronic lymphocytic leukemia (CLL) was the first disease that has been associated with the deregulation of microRNAs. In this study, the research team showed for the first time that lower levels of microRNA miR-29 in the tumor microenvironment increase the expression of its newly identified target namely TRAF4 (and enhance the CD40 signaling which is essential for proliferation of malignant B-cells. These results follow a series of high-profile papers in which Mraz lab has described the role of microRNAs in other microenvironmental interactions of B-cells.

The synergistic activation of B-cell receptor (BCR) and CD40 signalling via T-cell interactions is required for the proliferation of normal B-cells and malignant B-cells in CLL. However, it is largely unclear how this process is coordinated in B-cells. The research team showed that BCR signaling reduces miR-29 levels via MYC, thereby upregulating the TRAF4 levels and strengthening CD40 signaling. This study demonstrates that B-cells have a miRNA-dependent mechanism for coordinated regulation of BCR and CD40 signallingCD40. This has implications also for therapy.The ‘miR29-TRAF4’ loop is disrupted by clinically used BCR inhibitors (ibrutinib and idelalisib) which explains at least partially why these drugs affect proliferation of malignant B-cells and uncovers an unexpected mechanism of their action.  Moreover a synthetic miR-29 could be potentially used as a therapeutic agent, and a miR-29 mimic has already entered a clinical trial in non-haematological conditions.

The work would not be possible without the use of hundreds of primary samples from patients that were provided by collaborators in USA, Austria, and Czech Republic, and the study also utilized a mouse model for Myc activation. The project lasted about five years and involved many PhD students and postdoctoral researchers from Marek Mraz Research Group, as well as collaborators from abroad. This involved cooperation with many institutions namely University Hospital Brno, Medical University of Vienna, Dana-Farber Cancer Institute, and University of California-San Diego. . The publication was awarded as the best publication by the Czech Society of Hematology and MUNI Scientist Award for corresponding author Marek Mraz, and Vice-Rector Award for excellent achievements in doctoral studies at Masaryk University and Dean´s Award for the first author Sonali Sharma.