PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/ protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Reexpression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Reexpression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/ AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas. Diffuse large B-cell lymphoma (DLBCL) represents the most frequent lymphoma subtype and is considered a heterogeneous diagnostic category (1). Using gene expression profiling, two major molecular subtypes can be distinguished termed germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL (2). GCB DLBCLs are derived from germinal center B cells, whereas ABC DLBCLs originate from postgerminal center B cells that are in the transition of being differentiated into plasma cells. However, full plasma cell maturation is blocked in ABC DLBCL by different genetic abnormalities inhibiting the function of BLIMP1 that regulates plasmacytic differentiation (3-5).Recent work suggested constitutive activation of the PI3K/ protein kinase B (AKT) pathway that plays a crucial role in mediating growth, proliferation, and cell survival in a substantial number of DLBCL patient samples determined by immunohistochemical staining for phospho-AKT (p-AKT) (6, 7). However, these studies did not investigate the molecular mechanisms leading to constitutive PI3K/AKT signaling. The tumor suppressor PTEN is the major negative regulator of PI3K/AKT. PTEN functions as a lipid phosphatase dephosphorylating the 3′ position of phosphatidyl-inositol-3,-4,-5-trisphosphate, which serves as a trigger for AKT activation (8, 9). However, recent studies showed that PTEN has additional PI3K/AKT-independent tumor suppressor functions. Nuclear PTEN, for example, acts as guardian of genome integrity by up-...

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“…DLBCLs are known to be associated with the AKT signaling pathway, which is activated during carcinogenesis (33,34). Furthermore, AKT activation is associated with poor prognosis of DLBCL patients (35).…”

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

“…32,33 Genetic mutation and/or epigenetic silencing of PTEN have been observed in a large proportion of human B lymphomas, particularly in the diffuse large B cell lymphoma (DLBCL) subtype. 34 A potent inhibitory activity of schweinfurthins in mTOR-AKT activation suggested a potential high sensitivity of PTEN deficient DLBCL cells to schweinfurthins. Indeed, all 10 DLBCL cell lines that we tested showed great sensitivity, represented by IC 50 values (single digit nM) for SG after a 4 day treatment (Fig.…”

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

“…PI3K inhibition thus decreases MYC protein stability by releasing GSK3b from AKTmediated inactivation and therefore promoting MYC Thr58 phosphorylation and subsequent degradation (28)(29)(30)(31). Indeed, pharmacologic inhibition of the PI3K pathway is able to induce cell death in PTEN-deficient DLBCL cells as a result of MYC downregulation (32). PI3K inhibition also potentiates MYC downregulation and cell death in MYC-dependent NMC cells (33).…”