Inositol 1,4,5-trisphosphate 3-kinase B controls survival and prevents anergy in B cells

Maréchal, Yoann; Quéant, S.; Polizzi, Séléna; Pouillon, Valérie; Schurmans, Stéphane

doi:10.1016/j.imbio.2010.03.012

Cited by 14 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the above groups found that FcRγIIB inhibitory signals are compromised in SHIP −/− B cells, verifying earlier findings in B cell tumor lines that SHIP, rather than SHP1, is the inhibitory phosphatase recruited to FcγRIIB in B cells that inhibits B cell activation by immune complexes 38,63 . It merits mention that the Iptkb kinase that phosphorylates I(1,4,5)P 3 to generate I(1,3,4,5)P 4 has been shown to be critical for control of store‐regulated Ca 2+ channels and thus B cell anergy and activation 28,64,65 . Whether SHIP regulates intracellular Ca 2+ levels in B cells by hydrolysis of Iptkb‐produced I(1,3,4,5)P 4 is a possibility that might be examined as SHIP has been shown to also regulate Ca 2+ release following B cell activation 63 …”

Section: Ship In B Cell Functionsupporting

confidence: 77%

“…38,63 It merits mention that the Iptkb kinase that phosphorylates I(1,4,5)P 3 to generate I(1,3,4,5)P 4 has been shown to be critical for control of store-regulated Ca 2+ channels and thus B cell anergy and activation. 28,64,65 Whether SHIP regulates intracellular Ca 2+ levels in B cells by hydrolysis of Iptkb-produced I(1,3,4,5)P 4 is a possibility that might be examined as SHIP has been shown to also regulate Ca 2+ release following B cell activation. 63…”

Section: Ship In B Cell Functionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitor and activator: dual functions for SHIP in immunity and cancer

Kerr

2010

Annals of the New York Academy of Sciences

105

142

View full text Add to dashboard Cite

SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate BM graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system and immune cancers. Here I summarize how SHIP participates in normal immune physiology and the pathologies that result when SHIP is mutated. I also put forward a proposal that SHIP can have either inhibitory and activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P3) or its product (PI(3,4)P2) I also propose the “Two PIP Hypothesis” that postulates both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, I discuss potential therapeutic settings where chemical modulation of SHIP might be of benefit.

show abstract

Section: Ship In B Cell Functionsupporting

confidence: 77%

Section: Ship In B Cell Functionmentioning

confidence: 99%

Inhibitor and activator: dual functions for SHIP in immunity and cancer

Kerr

2010

Annals of the New York Academy of Sciences

105

142

View full text Add to dashboard Cite

show abstract

“…The 9 remaining genes represent novel candidate CLL drivers, with mutations occurring at highly conserved sites (Figure S1B). These included six genes with known roles in cancer biology ( NRAS, KRAS (Bos, 1989), BCOR (Grossmann et al, 2011), EGR2 (Unoki and Nakamura, 2003), MED12 (Makinen et al, 2011) and RIPK1 (Hosgood et al, 2009)), two genes that affect immune pathways (SAMHD1 (Rice et al, 2009), ITPKB (Marechal et al, 2011)) and a histone gene ( HIST1H1E (Alami et al, 2003)).…”

Section: Resultsmentioning

confidence: 99%

Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Landau

Carter

Stojanov

et al. 2013

Cell

1,248

1,279

View full text Add to dashboard Cite

Summary Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12 and del(13q)) or subclonal (e.g., SF3B1, TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two timepoints. Ten of 12 CLL cases treated with chemotherapy (but only 1 of 6 without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1, TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcome.

show abstract

“…The nine remaining genes represent candidate CLL drivers, with mutations occurring at highly conserved sites ( Figure S2). These included six genes with known roles in cancer biology (NRAS, KRAS [Bos, 1989], BCOR [Grossmann et al, 2011], EGR2 [Unoki and Nakamura, 2003], MED12 [Mä kinen et al, 2011], and RIPK1 [Hosgood et al, 2009]), two genes that affect immune pathways (SAMHD1 [Rice et al, 2009] and ITPKB [Maré chal et al, 2011]), and a histone gene (HIST1H1E [Alami et al, 2003]).…”

Section: Large-scale Wes Analysis Of Cll Expands the Compendium Of CLmentioning

confidence: 99%

The Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Landau

Carter

Stojanov

et al. 2012

Blood

118

153

View full text Add to dashboard Cite

5 The impact of clonal heterogeneity on cancer progression in chronic lymphocytic leukemia (CLL) is not well understood. We hypothesized that the evolutionary dynamics of subclonal mutations contribute to the variations in disease tempo and response to therapy that characterize CLL. We therefore carried out a large-scale analysis of subclonal and clonal point mutations and copy-number alterations in 149 CLLs, detected by whole exome sequencing (WES) and SNP arrays. We utilized a novel computational approach, which integrates purity and local ploidy information, to infer the cancer cell fraction (CCF) of each mutation from WES data, and to classify mutations as clonal or subclonal. Subclonal mutations were detected in 146/149 CLLs and were enriched with putative cancer driver events (P=0.001). Furthermore, higher numbers of subclonal mutations were associated with prior anti-leukemia therapy (P=0.017). Together, these results suggest that a strong extrinsic selection pressure, such as cytotoxic treatment, promotes the expansion of fitter subclones, driving them to above our detection threshold (CCF of ∼0.10). The order of mutation acquisition may be inferred from the aggregate frequencies at which driver events are clonal or subclonal, as clonal mutations represent earlier events and subclonal later events. Of the 149 samples, we found 3 drivers (MYD88, trisomy 12, and del(13q)) that were clonal in 80–100% of samples harboring these alterations –significantly higher than other driver events (q<0.1), suggesting that they arise earlier in typical CLL development. Other drivers (e.g., ATM, TP53 and SF3B1) were often observed at subclonal frequencies, indicating that they often arise later in leukemic development. We directly assessed the evolution of somatic mutations in 18 patients, in which data from two distant timepoints were available. Clonal evolution was observed in 11 of 18 patients (10 of 12 who received intervening treatment, but only 1 of 6 without intervening treatment, P=0.012) and confirmed that subclonal mutations (e.g., del(11q), SF3B1 and TP53) shifted towards clonality over time. Indeed, expanding subclonal mutations were enriched in putative drivers (P=0.021), suggesting that these mutations not only mark genetic evolution but also provide the fitness advantage driving it. Changes in the genetic composition of CLL cells with clonal evolution were associated with network level changes in gene expression. If treatment-associated genetic evolution leads to expansion of a fitter subclone, we would predict a shorter time to relapse in these individuals. Indeed, presence of a detectable subclonal driver mutation was associated with a shorter time to retreatment in these 18 samples (P=0.04), indicating that the presence of subclonal drivers adversely impacts clinical outcome. In the analysis of the full cohort of 149 samples, we observed that CLLs with subclonal driver mutations were associated with shorter times from diagnosis to first therapy (P=0.001) and between sample collection to treatment (P<0.001). Moreover, in the subset of 67 of 149 patients who were treated after sampling, presence of subclonal driver mutations evident in the pre-treatment sample was associated with earlier retreatment (P=0.003). Regression models adjusting for CLL prognostic factors (IGHV status, prior therapy and high risk cytogenetics) demonstrated that the presence of a subclonal driver was an independent risk factor for earlier retreatment (adjusted hazard ratio of 4.61 (CI 1.59–13.34), P=0.005). Thus, the detection of subclonal drivers(indicative of an active evolutionary process) is associated with shorter duration of remission. In conclusion, the analysis of clonal heterogeneity in CLL provides a glimpse into the past, present and future of a patient's disease. Through the cross-sectional analysis of 149 samples, we derived the number and genetic composition of clonal and subclonal mutations and thus uncovered footprints of the past history of CLL. Furthermore, we inferred a temporal order of genetic events implicated in CLL. Finally, our combined longitudinal and cross-sectional analyses revealed that knowledge of subclonal mutations anticipates the genetic composition of the future relapsing leukemia as well as the rapidity with which it will occur. These data challenge us to therapeutically address not only genetic targets but also their dynamic evolutionary landscape. Disclosures: No relevant conflicts of interest to declare.

show abstract

Inositol 1,4,5-trisphosphate 3-kinase B controls survival and prevents anergy in B cells

Cited by 14 publications

References 31 publications

Inhibitor and activator: dual functions for SHIP in immunity and cancer

Inhibitor and activator: dual functions for SHIP in immunity and cancer

Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

The Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About