The Notch pathway drives the ability of the bone marrow niche to promote RNA editing in multiple myeloma

Multiple myeloma (MM) is the second most frequently diagnosed hematological malignancy, and despite all the therapeutic advances it remains incurable due to the development of drug resistance. Recently, RNA editing has emerged as one of the important mechanisms that determines expression variability and therefore may be involved in the development of resistance to standard therapy. This process is mediated by adenosine deaminase acting on RNA (ADAR) enzymes that convert adenosines to inosines (A-->I editing) in double-stranded RNA (dsRNA) substrates. We hypothesize that ADAR1 activation in MM cells may be promoted by the normal cells of the bone marrow (BM) niche through the release of pro-tumor factor controlled by the oncogenic Notch pathway. Indeed, Notch is known to be hyperactivated in myeloma and it is crucial for the pathologic crosstalk between tumor cells and the surrounding BM microenvironment. Aim of this work was to investigate how the Notch pathway contributes to the ability of the BM microenvironment stromal cells on their ability to boost RNA editing and drug resistance in MM, in order to provide the rationale for a Notch-directed therapy that may allow to inhibit the progression of this disease.