The role of the transcription factor TCFL5 in the physiopathology of B lymphocytes

Resumen

Cancer is a major blight on health worldwide, being the second leading cause of death globally. It is based on the uncontrollable growth and reproduction of cells in a specific part of the body. Among the different processes that lead to the development of cancer hallmarks is the deregulation of transcription factors. Transcription factors are key players in several cellular processes and that is why their activity is altered in numerous cancer types. The MYC family of proto-oncogenes is one of the most studied given its recurrent appearance in a wide variety of cancers among which stand out B cell malignancies. Curiously, it is in this type of disease where a higher dysregulation of the expression of the Transcription Factor Like 5 (TCFL5) has been noted. TCFL5 is an insufficiently studied transcription factor despite the fact that several studies suggest it has an important role in spermatogenesis, the immune system and cancer. Although the work published so far describes only two isoforms for this human gene, known as TCFL5 and CHA, four more isoforms have been recently characterized. The development of tools that distinguish the isoforms allowed us not only to propose an important role of TCFL5 in the regulation of essential processes of B cells, but also to discriminate between the different isoforms while doing so. Even though the other isoforms did not show a clear relation with the severity of different types of blood cancer, the expression of TCFL5 and CHA was associated with greater severity in lymphoblastic and myeloid samples from patients. A role of TCFL5 in proliferation was elucidated with the generation of Ramos TCFL5 KO cells. The lack of TCFL5 caused a radical decrease in the levels of the most important molecules in BCR signalling, such as SYK and BLNK, resulting in an inability to respond to stimuli, an increase in cell death and an abnormal cell cycle. Furthermore, the results obtained suggest that TCFL5 is a target for LYN regulation where its activity is directly dependent on the expression of this kinase. The dual effect of TCFL5 on B cells was explained in the Raji lymphoma model where, by regulating MYC activity, two opposite functions of the gene isoforms were drawn: while TCFL5 promotes a tumor phenotype favouring MYC activity, CHA does the opposite. Its seems that TCFL5 and CHA are able to self-regulate and regulate each other shaping a regulatory loop with MYC in order to maintain the balance between the two isoforms and therefore cell normality. Last but not least, it was demonstrated that in murine models Tcfl5 is involved in the formation of germinal centers and in the stage of differentiation of pro-B to pre-B cells, two processes that are not only characterized by a high proliferation rate but also by being MYC dependent. This work suggests a crucial role for TCFL5 in the differentiation, maintenance and survival of B cells, which would explain the correlation between this transcription factor and the severity of leukemias and lymphomas, making it an attractive therapeutic target for these types of cancer