The approval of drugs that target the B cell receptor pathway (BCR) is an important step in the treatment of chronic lymphocytic leukaemia (CLL). However, the use of these novel drugs still does not lead to a cure and the patients relapse. The key question is how to combine BCR inhibitors with other drugs to achieve a cure or the “permanent” control of the disease. The design of smart combinatorial treatment of BCR-inhibitors requires gaining a full understanding of coding and non-coding RNA networks in B cells with inhibited BCR signalling. This proposal will take advantage of the possibility to analyse gene expression (Illumina) from primary B cells obtained directly from CLL patients both before and during the administration of BCR-inhibitors.
Objectives: i) To decipher how miRNAs and other non-coding RNAs regulate the BCR pathway in the context of microenvironmental interactions. These observations will likely be transferred to other B cell diseases and normal B cells. ii) To define the role of miRNAs in the regulation of BCR signalling in response to DNA damage, whose deregulation is associated with early relapses in BCR-inhibitors. The mechanisms that stop the pro-proliferative and anti-apoptotic signals from BCR after DNA damage are not yet known. iii) To use the knowledge of gene regulatory networks to reveal molecular inhibitors that should be used clinically in combination with BCRinhibitors. BCR-inhibitors are a very expensive (~€ 7 000/month) non-curative treatment, and there is a need for their combination with other drugs to achieve better disease control. The proposal has been previously submitted as a StartUp ERC grant and received very favourable comments (see below), however it was not funded. I aim to demonstrate that our approaches are feasible, novel, and improve the application by additional preliminary data to successfully re-apply for the ERC grant.

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