Early at the beginning of the project, I found that MITF is barely expressed in normal primary B cells, so as a sensible alternative, and according to the risks assessment foreseen, I focused on other relevant MiT family member, TFEB, unveiling that this transcription factor modulates b-cell fate downstream the RagC-nutrient signalling axis, having both, the lack of TFEB and the excess of TFEB activity a direct, but different, impact on B-cell differentiation and activation. While B cells with enhanced antigen-driven activation and increased capacity to undergo to GC reaction display suppression of TFEB activity, the constant activation of TFEB impairs the formation of GC upon immunization but originates spontaneous autoreactive B cells which formation may be related with an abnormal ISR activation.
Therefore, Objective 1 is just partly achieved, since due to the lack of time, I have not been able to dissect the precise crosstalk between TFEB activity and ISR either in the impairment of the GC formation or in B-cell spontaneous activation. Moreover, I have done very little progress to clarify how TFEB activation affects b-cell fatty acid metabolism. This question must be addressed in the next future.
As aforementioned, it has been impossible to assess the role of MITF and its interplay with ISR and fatty acid metabolism in B-cells, and the same is true for lymphomagenesis, but with the help of my supervisor, I have redirected my research to investigate the role of TFEB in lymphomagenesis. The preliminary data, mainly generated along these months, includes signatures of suppressed TFEB activity in Follicular Lymphomas with increased nutrient signalling, and increased cytoplasmic retention of TFEB in human Follicular Lymphomas samples with mutations in components of the nutrient signalling pathway (RagC), strongly suggest that, despite TFEB being reported as an oncogenic pathway in several epithelial tumours, this MiT transcription factor downstream of nutrient signalling may be a tumour suppressive for Follicular lymphoma.
Beyond the scientific goals, in this proposal I included specific training objectives addressed to foster my scientific development, aiming to promote my scientific independency in short-term, so, together, my supervisor and I, we designed a tailored career development plan to reinforce my competences at different levels.
