Mechanizmy patogenetyczne i cele terapeutyczne w chłoniaku rozlanym z dużych komórek B zależne od konstytutywnej aktywności tonicznej receptora B-komórkowego i programu transkrypcyjnego BCL6: od mikromacierzy DNA do racjonalnego leczenia
Year: 2009
Type: article
Abstract: Diffuse large B-cell lymphomas (DLBCL) are the most common lymphoid malignancy in adults and an extremely heterogeneous group of disorders. To delineate functionally relevant DLBCL subsets, consensus clustering methods were previously applied to the transcriptional profiles of two large independent series of primary DLBCL to identify the dominant substructure a priori. The obtained consensus clusters were highly reproducible and included a group of DLBCL, termed B-cell receptor (“BCR”) that was characterized by increased expression of components of the BCR signaling cascade including SYK (Spleen Tyrosine Kinase) and certain B-cell specific transcription factors such as BCL6; these DLBCL also exhibit more frequent translocations of the BCL6 locus. These observations suggested that the “BCR” molecular category of DLBCL might be reliant on either, or both, BCR signaling and BCL6 transcriptional program. To test this hypothesis, the studies were undertaken to specifically investigate the role of tonic SYK-dependent signaling in “BCR”-type DLBCL and the biological consequences of the pathway inhibition in vitro, mechanisms controlling SYK activity, role of transcriptional program controlled by BCL6 and the biological consequences of its inhibition in vitro and relationship between BCL6 mediated repression and SYK-dependent signaling in “BCR”-type DLBCL. These studies demonstrated that inhibition of the BCR signaling pathway with an ATPcompetitive inhibitor of SYK, R406, induced apoptosis of the majority of examined DLBCL cell lines and primary DLBCL in vitro. R406-sensitive DLBCL cell lines and primary tumors exhibited tonic activity of SYK and its direct substrate, B-cell linker protein (BLNK). In these R406-sensitive lines and primary tumors, R406 specifically inhibited both tonic and ligandinduced BCR signaling (SYK-dependent phosphorylation of BLNK). Therefore, SYK-dependent tonic BCR signaling is an important and potentially targetable survival pathway in some, but not all, DLBCL. In addition, R406-sensitive DLBCL can be identified by their transcriptional profiles. Consistent with critical role of SYK in modulating BCR signaling, its activity remains under tight control. SYK is a major substrate of a tissue-specific and developmentally regulated PTP, PTP receptor–type O truncated (PTPROt). The overexpression of PTPROt inhibited BCR-triggered SYK tyrosyl phosphorylation and downstream signaling events, including extracellular signal–regulated kinase (ERK1/2) activation. PTPROt overexpression also inhibited lymphoma cell proliferation and induced apoptosis in the absence of BCR cross-linking, suggesting that the phosphatase modulates tonic BCR signaling. “BCR” tumors also exhibit more abundant BCL6 expression and more frequent BCL6 translocations, suggesting that these tumors likely rely on BCL6 transcriptional program. It could be predicted therefore that DLBCL dependent upon BCL6-regulated pathways would exhibit coordinate repression of BCL6 target genes. For this reason, genomic array ChIP-on-chip was utilized to identify the cohort of direct BCL6 target genes. In primary DLBCL classified on the basis of gene expression profiles, these BCL6 target genes were differentially regulated in “BCR” tumors. In a panel of DLBCL cell lines analyzed by expression arrays and classified according to their gene expression profiles, only “BCR” tumors were highly sensitive to the BCL6 peptide inhibitor (BPI). These studies identify a discrete subset of DLBCL that are reliant upon BCL6 signaling and uniquely sensitive to BCL6 inhibitors. Since the same transcriptionally defined subset of DLBCL relies upon SYK-dependent BCR signaling and exhibits coordinate BCL6-mediated transcriptional repression, the relationship between these two processes was subsequently explored. In transcriptionally profiled normal B-cell subsets (naïve, germinal center [GC], and memory B cells) and in primary DLBCL, there were reciprocal patterns of expression of BCL6 and the SYK tyrosine phosphatase, PTPROt. BCL6 repressed PTPROt transcription via a direct interaction with functional BCL6 binding sites in PTPROt promoter. Enforced expression of BCL6 in normal naïve B cells and RNAi-mediated depletion of BCL6 in GC B-cells directly modulated PTPROt expression. In “BCR”-type DLBCL, BCL6 depletion increased PTPROt expression and decreased phosphorylation of SYK and the downstream adaptor protein, BLNK, demonstrating that BCL6 augments BCR signaling. Since BCL6 and SYK are both promising therapeutic targets in many DLBCL, combined inhibition of these functionally related pathways warrants further study.
Source: Via Medica Journals
Author: Dana Faber
Language: Polish
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2310182875