Efecto de la mutación L265P de la proteína adaptadora MyD88 en la migración celular del Linfoma Difuso de Células B Grandes

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma, accounting for the 40% of diagnosed cases worldwide. The heterogeneous nature of this disease is one of its main features and is directly related to the prognosis shown by the patients. There are many indicators linked to the development of the pathology but the most important one is the subtype of DLBCL present in the patient. The most extended classification distinguishes between germinal centre B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL. Both subtypes are defined by the differences detected in their genetic profile, that delineates not only the subtype but also the major mutations associated with each of them. ABC DLBCL associates with a worse prognosis, so specific compounds have been added to the treatment for fighting ABC DLBCL. Ibrutinib is one of those compounds, inhibitor of the kinase activity of Btk. ABC DLBCL neoplastic cells depend for their survival on the activation of the NF- kB pathway via Btk. Ibrutinib promotes neoplastic cell death by inhibiting Btk activity, and therefore NF- kB route. It has been shown to be effective in the treatment of ABC DLBCL, however, its effectiveness is reduced in the presence of the L265P mutation in the adaptor protein MyD88. This mutation allows MyD88 constitutive activation, promoting the assembly of the Btk signalosome and thus modulating Btk activity.The expression of the chemokine receptor CXCR4 is also related to a worse prognosis of the DLBCL. High CXCR4 expression levels at the cell surface are associated with a more aggressive nature of the tumour due to its involvement in cell migration and adhesion events. In addition, there is controversy about the involvement of Btk in the CXCR4-mediated functions.Taking into account the relevance of Btk and MyD88 in the development of ABC DLBCL, and that of CXCR4 in DLBCL, this work will evaluate the relationship between the three proteins in the molecular environment of the pathology and their functional effects on the development of the disease.