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Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma.

ABSTRACT: In addition to oncogenic MYC translocations, Burkitt lymphoma (BL) depends on the germinal centre (GC) dark zone (DZ) B cell survival and proliferation programme, which is characterized by relatively low PI3K-AKT activity. Paradoxically, PI3K-AKT activation facilitates MYC-driven lymphomagenesis in mice, and it has been proposed that PI3K-AKT activation is essential for BL. Here we show that the PI3K-AKT activity in primary BLs and BL cell lines does not exceed that of human non-neoplastic tonsillar GC DZ B cells. BLs were not sensitive to AKT1 knockdown, which induced massive cell death in pAKThigh DLBCL cell lines. Likewise, BL cell lines show low sensitivity to pan-AKT inhibitors. Moreover, hyper-activation of the PI3K-AKT pathway by overexpression of a constitutively active version of AKT (myrAKT) or knockdown of PTEN repressed the growth of BL cell lines. This was associated with increased AKT phosphorylation, NF-?B activation, and downregulation of DZ genes including the proto-oncogene MYB and the DZ marker CXCR4. In contrast to GCB-DLBCL, PTEN overexpression was tolerated by BL cell lines. We conclude that the molecular mechanisms instrumental to guarantee the survival of normal DZ B cells, including the tight regulation of the PTEN-PI3K-AKT axis, also operate in the survival/proliferation of BL.

SUBMITTER: Gehringer F

PROVIDER: S-EPMC7214272 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma.

Gehringer Franziska F Weissinger Stephanie Ellen SE Möller Peter P Wirth Thomas T Ushmorov Alexey A

Leukemia 20191112 3

In addition to oncogenic MYC translocations, Burkitt lymphoma (BL) depends on the germinal centre (GC) dark zone (DZ) B cell survival and proliferation programme, which is characterized by relatively low PI3K-AKT activity. Paradoxically, PI3K-AKT activation facilitates MYC-driven lymphomagenesis in mice, and it has been proposed that PI3K-AKT activation is essential for BL. Here we show that the PI3K-AKT activity in primary BLs and BL cell lines does not exceed that of human non-neoplastic tonsi ...[more]

PMID: 31719683

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Project description:Insulin/insulin-like growth factor signalling (IIS), acting primarily through the PI3-kinase (PI3K)/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K's direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten), in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight muscles, offering a new system to study the in vivo roles of IIS in the maintenance of mitochondrial integrity and adult ageing.

Dataset Information

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma.

Publications

Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma.

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