Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
Project description:ChIP-Sequencing of 4 diffuse large B-cell lymphoma cell lines expressing different amounts of FOXP1 was performed in order to identify target genes bound by the transcription factor FOXP1.
Project description:Expression of the forkhead transcription factor FOXP1 is essential for early B cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, being associated with poor prognosis. Here, by gene expression microarray [GSE51382] and quantitative RT-PCR analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation-sequencing (ChIP-seq), we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs but expression strongly decreases during plasma PC differentiation. Moreover, as compared to IgM+ MBCs, IgG+ MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant overexpression of FOXP1 might contribute to lymphomagenesis by blocking terminal B cell differentiation. OXP1 ChIP-seq profile in primary human memory B cells (MBCs) and B-cell lines
Project description:Gene expression profiling of diffuse large B-cell lymphoma (DLBCL)-derived cell lines exposed to the pan-PIM inhibitor MEN1703 was performed to investigate transcriptional consequences of PIM kinase inhibition in DLBCL and to identify treatment-related changes in the signalling pathways.
Project description:Fifty-eight retrospectively-ascertained local cases of diffuse large B-cell lymphoma (DLBCL) were segregated into two large subgroups with divergent overall survival through expression profiling of 135 transcripts including 92 regulated downstream of TCF3 or recurrently mutated in DLBCL or Burkitt lymphoma
Project description:Expression of the forkhead transcription factor FOXP1 is essential for early B cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, being associated with poor prognosis. Here, by gene expression microarray [GSE51382] and quantitative RT-PCR analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation-sequencing (ChIP-seq), we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs but expression strongly decreases during plasma PC differentiation. Moreover, as compared to IgM+ MBCs, IgG+ MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant overexpression of FOXP1 might contribute to lymphomagenesis by blocking terminal B cell differentiation.
Project description:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with at least one-third of its patients not responding to the current chemotherapy regimen, R-CHOP. By gene expression profiling, patients with DLBCL can be categorized into two clinically relevant subtypes: activated B-cell (ABC) DLBCL and germinal center B-cell (GCB). Patients with ABC DLBCL have a worse prognosis, and are defined by chronic, overactive signaling through the B-cell receptor and NF-κB pathways. We examined the effects of the Src family kinase (SFK) inhibitor dasatinib in a panel of ABC and GCB DLBCL cell lines, and found that the ABC DLBCL cell lines are much more sensitive to dasatinib than the GCB DLBCL cell lines. However, using multiplexed inhibitor bead coupled to mass spectrometry (MIB/MS) kinome profiling competition and western blot analysis, both subtypes display inhibition of the SFKs in response to dasatinib after both short- and long-term treatment. MIB/MS analyses revealed several cell cycle kinases, including CDK4, CDK6, and the Aurora kinases, are inhibited by dasatinib treatment in the ABC DLBCL subtype, but not in the GCB DLBCL subtype. The present findings have important implications for the clinical use of dasatinib for the treatment of ABC DLBCL, either alone or in combination with other agents.