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-...
Myeloid cell leukemia-1 (MCL1) is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared with germinal center B-cell-like DLBCL patient samples (P=2.7 × 10(-10)). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; P=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization data of 203 DLBCL samples and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1-positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.
Key Points• IkB-z is essential for nuclear NF-kB activity in ABC DLBCL.• ABC DLBCL survival depends on IkB-z signaling.Constitutive activation of the nuclear factor-k B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear IkB protein IkB-z to be upregulated in ABC compared with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IkB-z by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IkB-z knockdown demonstrated a significant downregulation of a large number of known NF-kB target genes, indicating an essential role of IkB-z in regulating a specific set of NF-kB target genes. To further investigate how IkB-z mediates NF-kB activity, we performed immunoprecipitations and detected a physical interaction of IkB-z with both p50 and p52 NFkB subunits, indicating that IkB-z interacts with components of both the canonical and the noncanonical NF-kB pathway in ABC DLBCL. Collectively, our data demonstrate that IkB-z is essential for nuclear NF-kB activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies. (Blood. 2013;122(13):2242-2250
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