PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones

Sander, Sandrine; Chu, Van Trung; Yasuda, Tomoharu; Franklin, Andrew; Graf, Robin; Calado, Dinis Pedro; Li, Shuang; Imami, Koshi; Selbach, Matthias; Virgilio, Michela Di; Bullinger, Lars; Rajewsky, Klaus

doi:10.1016/j.immuni.2015.10.021

Cited by 216 publications

(333 citation statements)

References 53 publications

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“…For instance, immunotoxins and other anticancer drugs with a biologic compocin-treated mice. We should note, however, that our examination of available gene expression data sets for GC B cell subpopulations failed to uncover enrichment for known mTORC1 target genes within centroblasts (42). Likewise, using a multiplexed single-cell RT-PCR approach, we did not uncover enrichment of mRNA transcripts for numerous mTORC1 targets, including Rps6, Eif4e, Gpi1, and Ldha (data not shown).…”

Section: Discussionmentioning

confidence: 67%

mTOR has distinct functions in generating versus sustaining humoral immunity

Jones¹,

Gaudette²,

Wilmore³

et al. 2016

Journal of Clinical Investigation

137

135

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. multiple comparisons, the Kruskal-Wallis test was used with Dunn's multiple comparison test. For qRT-PCR studies, the Shapiro-Wilk test was used to confirm a normal distribution for the resulting data. In each case, P values less than 0.05 were considered significant. Study approval. All animal studies described herein were reviewed and approved by the University of Pennsylvania IACUC. Animals were bred and maintained in accordance with institutional guidelines for animal welfare.

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Section: Discussionmentioning

confidence: 67%

mTOR has distinct functions in generating versus sustaining humoral immunity

Jones¹,

Gaudette²,

Wilmore³

et al. 2016

Journal of Clinical Investigation

137

135

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show abstract

“…24 Likewise, N-terminally clustered mutations in FOXO1 25 might affect response to inhibitors of the phosphatidylinositol 39 OH kinase (PI3K) pathway, given that FOXO transcription factors and PI3K often function as antagonists in the biology of B cells. 26 Eventually, the relative impact of individual molecular predictors will have to be adjusted to specific molecular targeting approaches; for example, CARD11 mutations have a relatively small m7-FLIPI coefficient in the context of immunochemotherapy, but they might well increase the risk of treatment failure in patients receiving BTK inhibitors by activating NF-kB signaling downstream of BTK, as has been shown for ibrutinib for relapsed/refractory diffuse large B-cell lymphoma. 27 Several large and collaborative efforts are underway to address these questions.…”

Section: Discussionmentioning

confidence: 99%

Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy

Jurinović

Kridel

Staiger

et al. 2016

Blood

190

145

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• The posttreatment end point progression of FL within 24 months (POD24) is strongly associated with OS.• A pretreatment clinicogenetic risk model (m7-FLIPI) predicts POD24 and OS and identifies the smallest subgroup with highest unmet need.Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P < .0001) and 26% (vs 86%, P < .0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P 5 .00031) and 4.76 in BCCA patients (P 5 .0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL. (Blood. 2016; 128(8):1112-1120

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“…In mouse GCs, PI3K activity is restricted to the light zone while nuclear Foxo1 is largely absent. A fraction of cells in the light zone that do express Foxo1 are destined for dark zone re-entry as Foxo1 is needed to instruct the dark zone gene program including the chemokine receptor Cxcr4 (Dominguez-Sola et al, 2015; Sander et al, 2015). Foxo1 deletion or increased PI3K activity lead to loss of architectural polarity and lack of dark zones while impairing SHM and class switching.…”

Section: Pi3k In Innate and Adaptive Immunitymentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,886

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones

Cited by 216 publications

References 53 publications

mTOR has distinct functions in generating versus sustaining humoral immunity

mTOR has distinct functions in generating versus sustaining humoral immunity

Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy

The PI3K Pathway in Human Disease

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