Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/ -catenin genes in human herpesvirus 8-associated primary effusion lymphoma

Boulanger, Emmanuelle; Marchio, Agnès; Hong, Saw-See; Pineau, Pascal

doi:10.3324/haematol.2009.007260

Cited by 25 publications

(28 citation statements)

References 23 publications

(23 reference statements)

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“…For example, at least 10 cases of HIV-negative patients with primary effusion lymphoma were found to be without EBV coinfection. 3,[21][22][23][24] Different from the reported CD20 expression among all seven EBVnegative primary effusion lymphoma cases from Japan, 24 CD20 was not expressed in any of our four EBV-negative primary effusion lymphoma cases.…”

Section: Discussioncontrasting

confidence: 48%

“…For instance, EBV was not detected in 1 out of 12 and 3 out of 12 HHV-8-associated primary effusion lymphoma in HIVpositive patients. 21,22 Furthermore, absence of EBV coinfection tends to be more prevalent in primary effusion lymphoma in HIV-negative patients. For example, at least 10 cases of HIV-negative patients with primary effusion lymphoma were found to be without EBV coinfection.…”

Section: Discussionmentioning

confidence: 99%

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Notch1 in primary effusion lymphoma: a clinicopathological study

Wang¹,

Fuda²,

Chen³

et al. 2010

Modern Pathology

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Notch1 in primary effusion lymphoma: a clinicopathological study

Wang¹,

Fuda²,

Chen³

et al. 2010

Modern Pathology

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“…10 No activating PI3K mutations have been reported in PEL, and only 2 PEL lines display PTEN mutations. 22 This suggests that in PEL constitutive activation of PI3K, Akt, and mTOR kinases is the result of the expression of viral proteins. We previously reported that treatment with rapamycin, an mTOR inhibitor, induces cell cycle arrest in PEL and may halt clinical progression.…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Bhatt

Bhende

Sin

et al. 2010

Blood

131

126

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Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcomaassociated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. IntroductionThe phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and cell survival. PI3K activation stimulates the production of phosphatidylinositol 3,4,5-triphosphate, which results in activation of the kinases PDK1 and Akt. The lipid phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is a negative regulator of this pathway. Akt kinase promotes cell survival by phosphorylating, and thereby inactivating, proapoptotic factors, such as the FOXO transcription factor family, GSK-3␤, caspase-9, and Bad. [1][2][3][4] Phosphorylation of Bad and the FOXO transactivators prevent apoptosis. Akt also phosphorylates p27, a negative regulator of the cell cycle, thereby preventing cell cycle arrest. In addition, Akt activation leads to phosphorylation and activation of the mammalian target of rapamycin (mTOR), a kinase that stimulates protein synthesis and cell proliferation.Activated mTOR protein can associate with raptor and mLST8/G␤L to form the mTORC1 complex. The mTORC1 complex induces phosphorylation of p70 S6 kinase (S6K), leading to phosphorylation and activation of the ribosomal protein S6. mTORC1 also inhibits 4E-BP1, a repressor of eukaryotic initiation factor eIF4E. This arm of the mTOR pathway is rapamycin-sensitive. In contrast, the mTORC2 complex, which consists of mTOR, mLST8/G␤L, mSin1, and Rictor, is insensitive to the effects of rapamycin. mTORC2 functions in a feedback loop that phosphorylates and activates Akt by phosphorylation at Ser473. 5 Hence, inhibitors of PI3K/Akt probably have broader effects than mTOR inhibitors.The nutrient sensor, AMP activated kinase (AMPK), is a negative regulator of mTORC1. 6 AMPK controls cellular homeostasis by regulating energy production withi...

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“…The p53 tumor suppressor protein appears functional in PEL cell lines, 15 the Myc locus un-rearranged, although the protein is unusually stable, 16 and no amplifications or deletions are reported for Bcl-2, 2 Bcl-6, 17 Ras, 2 the catalytic subunit of PI3K, 18 phosphatase with tensin homolog or p16/INK4. 18 We therefore used the Affymetrix 6.0 single nucleotide polymorphism (SNP)-based microarray to conduct comparative genomic hybridization (CGH) to look at the global genomic profile of PEL cells. This identified PEL-specific gene alterations in the fragile site tumor suppressor genes, fragile histidine triad (FHIT) and WW-domain containing oxidoreductase (WWOX), which were deleted in 11 of 13 (85%) and 12 of 13 (92%) samples, respectively (P Յ .0005).…”

Section: Introductionmentioning

confidence: 99%