B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)-encoding genes produce a functional B cell receptor (BCR) and antibodies. As part of this process, recombination-activating gene (Rag) proteins regulate the in-frame assembly of the Ig-encoding genes. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)-containing Igalpha and Igbeta chains. Whereas the activation of the tyrosine kinases Src and Syk is essential for BCR signaling, the pathways that act downstream of these kinases are incompletely defined. Previous work has revealed a key role for the p110delta isoform of phosphatidylinositol 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on agonist-independent or "tonic" BCR signaling, are not substantially affected by a deficiency in p110delta. Here, we show that p110alpha, but not p110beta, compensated in the absence of p110delta to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110alpha and p110delta activities, pre-BCR signaling failed to suppress the production of Rag proteins and to promote developmental progression of B cell progenitors. Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling. These studies indicate that either p110alpha or p110delta can mediate tonic signaling from the BCR, but only p110delta can contribute to antigen-dependent activation of B cells.
"The development of early B cells in BM represents a paradigm for a terminal differentiation process involving the step-wise conversion of a multipotent stem cell into a highly specialized cell type. Previous studies have demonstrated a key role for phosphatidylinositol 3-kinase (PI3K) signaling in this process , , , . PI3Ks form a family of lipid kinase enzymes that generate 3′-phosphorylated phosphoinositides. "
[Show abstract][Hide abstract] ABSTRACT: The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1.
PLoS ONE 08/2014; 9(8):e103970. DOI:10.1371/journal.pone.0103970 · 3.23 Impact Factor
"In addition to the productive rearrangements required to produce the pre-BCR, pre-B cell development in the mouse also requires signaling through the IL-7R, as mice lacking signaling components of the IL-7 receptor have few pre-B cells (Peschon et al. 1994; Clark et al. 2014). Similarly, absence of the signaling cascade components that follow IL-7R activation such as STAT5 (A and B) (Goetz et al. 2004; Yao et al. 2006), cyclin D3 (Cooper et al. 2006), and phosphoinositide 3-kinase (PI3K) (Ramadani et al. 2010; Fruman et al. 1999; Suzuki et al. 1999; Clayton et al. 2002; Jou et al. 2002; Okkenhaug et al. 2002) greatly attenuate the proliferation and survival of pre-B cells. Interestingly, mutation in ATP11c, a P4 ATPases (flippase) that is required for IL-7 signaling, results in a progressive loss of pro-and pre-B cells (Clark 2011; Pang and Nutt 2011; Siggs et al. 2011; Yabas et al. 2011). "
[Show abstract][Hide abstract] ABSTRACT: The differentiation of early B cell progenitors is controlled by multiple transcriptional regulators and growth-factor receptors. The triad of DNA-binding proteins, E2A, EBF1, and PAX5 is critical for both the early specification and commitment of B cell progenitors, while a larger number of secondary determinants, such as members of the Ikaros, ETS, Runx, and IRF families have more direct roles in promoting stage-specific pre-B gene-expression program. Importantly, it is now apparent that mutations in many of these transcription factors are associated with the progression to acute lymphoblastic leukemia. In this review, we focus on recent studies that have shed light on the transcriptional hierarchy that controls efficient B cell commitment and differentiation as well as focus on the oncogenic consequences of the loss of many of the same factors.
Current topics in microbiology and immunology 05/2014; 381. DOI:10.1007/82_2014_377 · 4.10 Impact Factor
"Activation of downstream pathways is initiated by the recruitment of effector molecules such as PDK1, Akt, Btk, and PLCg2, which bear pleckstrin homology (PH) domains that directly bind PtdIns(3,4,5)P 3 (Baracho et al., 2011). p110d-deficient B cells exhibit impaired BAFF-induced survival (Henley et al., 2008), and combined inactivation of p110a/d results in failed B cell generation or accumulation (Ramadani et al., 2010). Using Akt phosphorylation as a surrogate readout, investigators have observed that BAFF induces PI3K activity with both rapid and delayed kinetics (Otipoby et al., 2008; Patke et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
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