Fbxw7 Is Critical For B1 Cell Maintenance And Function

Background: The E3 ubiquitin ligase Fbxw7 is responsible for the proteasomal degradation of several oncogenes involved in cellular proliferation, growth and survival. Notably, Fbxw7 has been characterized as a tumor suppressor in a variety of cancers, including T ALL and CLL. In the absence of Fbxw7, hematopoiesis is defective leading to abnormal development of B and T cells. In these mice, hematopoietic stem cells have impaired self-renewal due to stabilization of c-Myc. Fbxw7 targets several well-characterized molecules (c-Myc, Mcl1, p100, cyclin E, mTOR, SREBP1) with essential functions in B cells. We have recently shown that glycogen synthase kinase 3 (Gsk3), which is negatively regulated by PI3K signaling, controls the metabolic needs of B cells (Jellusova et al., 2017 Nat. Immunol.). A number of Gsk3 substrates are phosphorylated and degraded via the proteasome through recognition of Fbxw7. We sought to investigate the GSK3-FBXW7 axis in B cells and its implications for B cell malignancies.