Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

Miletic, Ana V.; Anzelon-Mills, Amy N.; Mills, David; Omori, Sidne A.; Pedersen, Irene M.; Shin, Dong‐Mi; Ravetch, Jeffrey V.; Bolland, Silvia; Morse, Herbert C.; Rickert, Robert C.

doi:10.1084/jem.20091962

Cited by 79 publications

(49 citation statements)

References 57 publications

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“…These results are consistent with data, suggesting that signaling through the PI3K pathway, in particular downstream of the pre-BCR, is important for early B cell development especially for the survival and differentiation of pre-B cells (Werner et al, 2010). Furthermore, increased PTEN expression in the absence of miRNAs may also contribute to the elevated level of the pro-apoptotic protein Bim (Miletic et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

et al. 2016

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SUMMARY B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.

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Section: Discussionmentioning

confidence: 99%

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

et al. 2016

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“…B cell purification and in vitro stimulation were performed as described (Miletic et al, 2010). For survival assays, purified splenic or lymph node B cells were plated at a concentration of 1×10 6 cells/mL in 10% media.…”

Section: Methodsmentioning

confidence: 99%

Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

et al. 2013

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Summary BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the non-canonical 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 PI3K, and that co-inactivation 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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“…In vivo studies of the impact of BAFF depletion on lymphoma progression are limited. However, we found that primary B cells tumors arising from the co-inactivation of Pten and Ship can progress in the absence of BAFF (138). Thus, based on murine models, one may predict that malignant B cells displaying constitutive activation of canonical or non-canonical NF-κB or PI3K may not be responsive to anti-BAFF treatment.…”

Section: Baff-r Signaling and Diseasementioning

confidence: 97%

Signaling by the tumor necrosis factor receptor superfamily in B‐cell biology and disease

Rickert

Jellusova

Miletic

2011

Immunological Reviews

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265

256

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Summary Members of the tumor necrosis factor receptor superfamily (TNFRSF) participate prominently in B-cell maturation and function. In particular, B-cell activating factor belonging to the TNFR family receptor (BAFF-R), B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) play critical roles in promoting B-cell survival at distinct stages of development by engaging a proliferation-inducing ligand (APRIL) and/or BAFF. CD40 is also essential for directing the humoral response to T-cell-dependent antigens. Signaling by the TNFRSF is mediated primarily, albeit not exclusively, via the TNFR-associated factor (TRAF) proteins and activation of the canonical and/or noncanonical nuclear factor-κB (NF-κB) pathways. Dysregulated signaling by TNFRSF members can promote B-cell survival and proliferation, causing autoimmunity and neoplasia. In this review, we present a current understanding of the functions of and distinctions between APRIL/BAFF signaling by their respective receptors expressed on particular B-cell subsets. These findings are compared and contrasted with CD40 signaling, which employs similar signaling conduits to achieve distinct cellular outcomes in the context of the germinal center response. We also underscore how new findings and conceptual insights in TNFRSF signaling are facilitating the understanding of B-cell malignancies and autoimmune diseases.

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Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

Abstract: Mice lacking both PTEN and SHIP phosphatases develop spontaneous B cell lymphoma.

Cited by 79 publications

References 57 publications

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation

Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

Signaling by the tumor necrosis factor receptor superfamily in B‐cell biology and disease

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