Kurzfassung

B-lymphocytes are responsible for the humoral antibody response against a wide range of pathogens. The development of these cells has been studied intensively in the last decades and comprised of an ordered cascade of events that starts in the bone marrow and following positive and negative selection processes culminates in the development of mature B cells in the periphery that have minimal self-reactivity. Upon encounter with antigens, mature B cells differentiate into plasma cells that...B-lymphocytes are responsible for the humoral antibody response against a wide range of pathogens. The development of these cells has been studied intensively in the last decades and comprised of an ordered cascade of events that starts in the bone marrow and following positive and negative selection processes culminates in the development of mature B cells in the periphery that have minimal self-reactivity. Upon encounter with antigens, mature B cells differentiate into plasma cells that secrete copious amount of antibodies and give rise to a pool of memory cells important for a recall response [1]. In the spleen mature B cells populate two anatomically distinct locations: follicles (FL) and marginal zone (MZ). Not surprisingly, FL and MZ B cells have distinct phenotypes and functions [2].
In a nutshell, the PI3K/AKT/mTOR signaling pathway is activated by multiple stimulations including tyrosine kinase receptors and many other cell surface receptors. This signaling pathway involves initially the activation of PI3K, a large family of enzymes that catalyze the generation of phosphoinositides that activate AKT, a serine/threonine kinase which has many cellular substrates. PI3K activity is strongly counteracted by the phosphoinositide phosphatase PTEN. Thus, loss of PTEN activity leads to robust activation of the PI3K/AKT/mTOR signaling pathway from its most upstream event. Once AKT is activated, one of its main substrates is the tuberous sclerosis complex 2 subunit (TSC2). Phosphorylation of TSC2 by AKT leads to the activation of the mTOR, also a serine/threonine kinase, which controls many of the metabolic activities of the cell.  Because activation of the PI3K/AKT/mTOR pathway typically results in hyperproliferation and better endurance of hypoxic conditions and lack of nutrients, gain of function mutations in this pathway are found in high percentage of the tumors [3]. Furthermore, under normal conditions each step of the signaling is carefully balanced by an intricate network of negative feedbacks, thus dysregulation at distinct elements along the signaling cascade may result in a large spectrum of phenotypes Therefore, mechanistic understanding of the phenotype requires more than one manipulation,
PI3K/AKT/mTOR signaling pathway is activated downstream to the B cell receptor (BCR). To explore the role of PI3K/AKT/mTOR signaling pathway in B cell development, function and transformation into lymphomas several approaches have been described. Deletion of PTEN in the B cell lineage caused an increase in MZ B cells, but was not sufficient to cause lymphomas [4].  In a second study a catalytically active mutant of PI3K was expressed in the B cell lineage and provided evidence that PI3K signal is essential for mature B cell survival. Interestingly, the FOXO1 transcription factor downstream to AKT played a central role in this effect rather than the mTOR. Again, no evidence for B cell lymphomas was seen in this model, unless other pathways were simultaneously activated such as the Myc oncogene [5], [6]. Because these reported mouse models activated the pathway upstream in the signaling cascade, we reasoned that the relative mild phenotypes seen in them were due to mitigation by downstream checks and balances.» weiterlesen» einklappen