Regulation of B cell differentiation and metabolism by the phosphoinositide 3-kinase (PI3K) pathway. PI3K signaling is essential for B cell generation and activation, and small molecule inhibitors of the PI3Kδ isoform have been recently approved for the treatment of indolent B cell malignancies. A major effort in the lab is to understand how components of the PI3K signaling pathway specifically contribute to B cell growth, proliferation and survival as well as functions unique to B cells, namely antigen receptor assembly, signaling and antibody production (Baracho et al.). Activation of the PI3K signaling network recruits cytosolic effectors to the plasma membrane via pleckstrin homology (PH) domain-binding to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). In particular, PDK1 has been identified as a pivotal downstream effector of PI3K that activates Akt, p70S6kinase, PKC enzymes and other targets that control cell metabolism, quiescence, proliferation and survival (Baracho et al.). Akt is thought to be critical for the inactivation of GSK3, which targets proteins for phosphorylation-dependent degradation. Akt has also been shown to negatively regulate the activity of the FOXO transcription factors, where we have shown that FOXO1 is selectively required for many critical B cell-specific functions (Dengler et al.). While much of the interest in PI3K in B cells has focused on BCR-induced signaling events, we also have a keen interest in the importance of this pathway in responses to key microenvironmental factors such as BAFF.
B cell stage-specific functions of the NIK/IKK1 axis. NIK and its substrate IKK1 are closely aligned with the non-canonical NF-κB pathway and generation of p52/RelB heterodimers. This paradigm holds true for late B cell maturation, which requires BAFF-dependent signaling via the non-canonical pathway. However, we found that IKK1 is largely dispensable for the acute survival of mature recirculating B cells (Jellusova et al.). In the germinal center, the NIK/IKK1 axis again becomes critical in B cells (Mills et al.), although it appears to function independently of p52/RelB activity. The IKK2-dependent canonical NF-κB pathway is also important for B cell activation downstream of the BCR and the CARD11/BCL10/MALT1 (CBM) complex (Rickert). We are investigating the NF-κB pathways to gain insight into how signaling requirements change during B cell differentiation.
New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. R.C. Rickert. Nat. Rev. Immunol. 13, 578–591 (2013).
B cell lymphomagenesis and progression. Most aggressive B cell non-Hodgkin lymphomas (B-NHL) are germinal center-derived. New insights into the critical signaling pathways and effectors that regulate B cell fate at this stage will provide new avenues to explore cancer-relevant signaling nodes and checkpoints. For example, we found that the inositol phosphatases PTEN and SHIP work cooperatively to suppress B lymphomagenesis (Miletic et al.). With the goal of understanding the etiology and treatment of particular subtypes of B-NHL, we are particularly interested in determining the predisposing genetic factors and microenvironmental stimuli that drive lymphoma progression.