Phosphatase and tensin homolog ( PTEN ) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency

Tsujita, Yuki; Mitsui-Sekinaka, Kanako; Imai, Kohsuke; Yeh, Ta‐Sen; Mitsuiki, Noriko; Asano, Takaki; Ohnishi, Hiroyuki; Kato, Zenichiro; Sekinaka, Yujin; Zaha, Kiyotaka; Kato, Tamaki; Okano, Toshio; Takashima, Takehiro; Kobayashi, Kaoru; Kimura, Mitsuaki; Kunitsu, Tomoaki; Maruo, Yoshihiro; Kanegane, Hirokazu; Takagi, Motoki; Yoshida, Kenichi; Okuno, Yusuke; Muramatsu, Hideki; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Kojima, Seiji; Ogawa, Seishi; Ohara, Osamu; Okada, Satoshi; Kobayashi, Masao; Morio, Tomohiro; Nonoyama, Shigeaki

doi:10.1016/j.jaci.2016.03.055

Cited by 86 publications

(87 citation statements)

References 30 publications

(17 reference statements)

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“…Although the CD19 + B220 − B cells we describe resemble B1 cells by some criteria, such as the expression of CD5 and CD43, their lower IgM expression, lack of B220 and distribution pattern suggest that they are related but distinct to conventional B1 and B10 cells 30, 31 . A similar subset has previously been described as being dependent on CD19 and increased in the absence of PTEN expression and PTEN haploinsuffiency in humans can lead to an APDS-like syndrome 38–40 .…”

Section: Discussionsupporting

confidence: 58%

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

Stark

Chandra

Chakraborty

et al. 2018

Preprint

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Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death 1world-wide. Antibody-mediated immune responses can offer protection against repeated 2 exposure to S. pneumoniae, yet vaccines only offer partial protection. Patients with 3 Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated 4 a conditional knockin mouse model of this disease and identified a CD19 + B220 -B cell 5 subset that is induced by PI3Kδ signaling, is resident in the lungs, and which promotes 6 increased susceptibility to S. pneumoniae during the early phase of infection via an 7 antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves 8 survival rates following S. pneumoniae infection in wild-type mice and in mice with 9 activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the 10 severity of S. pneumoniae infection, representing a novel therapeutic target. 11 100 2B). This pattern resembles results found in patients with APDS 10 . In wild-type and 101 p110δ E1020K-GL cells, the PI3Kδ-selective inhibitor nemiralisib reduced PIP3 to the background 102 level observed in p110δ D910A cells, which, as expected, were insensitive to nemiralisib ( Fig 103 2A, B). 104 105 PIP3 binds to the protein kinase AKT, supporting its phosphorylation on Thr308 and 106 subsequent activation. Western blotting of purified p110δ E1020K-GL T cells showed increased 107AKT phosphorylation following stimulation with anti-CD3 and anti-CD28 antibodies 108 compared to wild-type cells, whereas AKT phosphorylation in p110δ D910A T cells was below 109 the limit of detection ( Fig 2C). In B cells, both basal and anti-IgM-induced phosphorylation of 110 AKT were elevated in p110δ E1020K-GL cells, while strongly diminished in p110δ D910A B cells (Fig 111 2D). The phosphorylation of ERK and the AKT effector proteins, FOXO and S6, were similarly 112 affected. All phosphorylation events in wild-type and p110δ E1020K-GL cells were reduced to 113 the levels observed in p110δ D910A cells by inhibition with nemiralisib. As expected, p110δ 114 protein expression was not affected by the E1020K or D910A mutations (Figs 2C, D). 115 116

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Section: Discussionsupporting

confidence: 58%

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

Stark

Chandra

Chakraborty

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Here we use the generic term APDS unless referring specifically to either. A milder form of APDS-like immunodeficiency has been described in Cowden disease, caused by heterozygous loss of PTEN, although the increases in PIP 3 and pAKT levels from these patient T cells was less obvious than observed in the T cells from patients with APDS69, 75.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 84%

“…Subsequently, a number of additional studies have identified APDS patients with mutations in PIK3CD 5, 7, 64–69 or PIK3R1 6, 70–73. Patients with GOF mutations in either of these genes appear to largely phenocopy each other, despite the fact that p85α is ubiquitously expressed and can pair with p110α and p110β in addition to p110δ.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

PI3Kδ and primary immunodeficiencies

et al. 2016

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Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

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“…In general, MTORC1 regulates cell autonomous growth by controlling nutrient availability and growth factors, whereas MTORC2 mediates cell proliferation and survival by regulating cell surface area (45,49). Dysregulation of upstream signals, such as PI3K/AKT mutation (50), Phosphatase and tensin homolog (PTEN) mutation (51), Tuberous sclerosis complex (TSC) loss of function (52), and RAS mutation (53), often results in the alteration of MTOR, which has been demonstrated to contribute to a poor prognosis in serious cancers including NSCLC, breast cancer, gastric cancer and esophageal squamous cell carcinoma (54–57). The activation of MTOR is mediated by Ser2448 phosphorylation through the PI3K/AKT/MTOR pathway, and then it activates a potent oncogene, EIF4E (58).…”

Section: Discussionmentioning

confidence: 99%

TRIM59 is a novel potential prognostic biomarker in patients with non-small cell lung cancer: A research based on bioinformatics analysis

Hao

2017

Oncology Letters

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Lung cancer is the leading cause of cancer-associated mortality worldwide and its prognosis is poor. Few effective biomarkers for non-small cell lung cancer (NSCLC) have been translated into the clinical practice aiming to assist in the treatment plan design and prognosis evaluation. The aim of the present study was to identify novel potential prognostic biomarkers for NSCLC. Tripartite motif 59 (TRIM59) was identified from a microarray dataset of matched-samples and was verified as an aberrantly upregulated gene in NSCLC tissue. The expression level of TRIM59 in NSCLC subtypes was observed to be significantly increased in large cell lung carcinoma and squamous cell carcinoma as compared with that in adenocarcinoma. Its expression correlated with several clinicopathological features, including gender, smoking habits, and unfavorable tumor node and pathological stages. Notably, TRIM59 demonstrated a negative correlation with survival time and its overexpression indicated a poor prognosis in NSCLC. Furthermore, univariate and multivariate Cox's regression analyses indicated that TRIM59 was an independent prognostic factor in tumor tissue as compared with age, gender, tumor stage, node stage, and metastasis. Gene set enrichment analysis and protein-protein interaction network construction revealed that TRIM59 was associated with oncogenic mammalian target of rapamycin (MTOR) and eukaryotic initiation factor 4E (EIF4E) signaling through ubiquitin C binding. In conclusion, it was revealed that TRIM59 is a novel prognostic biomarker modulating oncogenic MTOR and EIF4E signaling pathways in NSCLC. These findings provided a novel insight into the clinical application of TRIM59. Therefore, TRIM59 may serve as an independent predictor for prognosis and a potential therapeutic target for NSCLC.

show abstract

Phosphatase and tensin homolog ( PTEN ) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency

Abstract: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

Cited by 86 publications

References 30 publications

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

PI3Kδ and primary immunodeficiencies

TRIM59 is a novel potential prognostic biomarker in patients with non-small cell lung cancer: A research based on bioinformatics analysis

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