Reprogramming Specific Gene Expression Pathways in B-Cell Lymphomas

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex interplay among immune cell types. SLE activity is experimentally assessed by several blood tests, including gene expression profiling of heterogeneous populations of cells in peripheral blood. To better understand the contribution of different cell types in SLE pathogenesis, we applied the two methods in cell-type-specific differential expression analysis, csSAM and DSection, to identify cell-type-specific gene expression differences in heterogeneous gene expression measures obtained using RNA-seq technology. We identified B-cell-, monocyte-, and neutrophil-specific gene expression differences. Immunoglobulin-coding gene expression was altered in B-cells, while a ribosomal signature was prominent in monocytes. On the contrary, genes differentially expressed in the heterogeneous mixture of cells did not show any functional enrichment. Our results identify antigen binding and structural constituents of ribosomes as functions altered by B-cell- and monocyte-specific gene expression differences, respectively. Finally, these results position both csSAM and DSection methods as viable techniques for cell-type-specific differential expression analysis, which may help uncover pathogenic, cell-type-specific processes in SLE.

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Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study

Blood ◽

10.1182/blood-2009-10-247122 ◽

2010 ◽

Vol 116 (7) ◽

pp. 1092-1104 ◽

Cited By ~ 72

Author(s):

Fabrice Jardin ◽

Jean-Philippe Jais ◽

Thierry-Jo Molina ◽

Françoise Parmentier ◽

Jean-Michel Picquenot ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Gene Expression Signature ◽

Gene Copy ◽

Specific Gene ◽

B Cell Lymphomas ◽

Single Polymerase Chain Reaction ◽

Expression Signature ◽

Cdkn2a Deletion ◽

Large B Cell

Abstract Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

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Uniform Expression of Notch1, Suppressor of B-Cell–Specific Gene Expression, in Plasmablastic Lymphoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/2009-0691-oa.1 ◽

2011 ◽

Vol 135 (6) ◽

pp. 770-775

Author(s):

Adam C. Seegmiller ◽

Huan-You Wang ◽

Christa Hladik ◽

Weina Chen

Keyword(s):

Gene Expression ◽

B Cell ◽

Plasma Cell ◽

Primary Effusion Lymphoma ◽

Mtor Pathway ◽

Plasmablastic Lymphoma ◽

Cell Phenotype ◽

Specific Gene ◽

Plasma Cell Myeloma ◽

Specific Gene Expression

Abstract Context.—Although the loss of B-lineage–specific gene expression is a distinctive feature of plasmablastic lymphoma, the underlying mechanism remains poorly understood. A candidate for this mechanism is Notch1 signaling, which interferes with the activity of B-cell–specific transcription factors E2A and early B-cell factor and positively regulates the mammalian target of rapamycin (mTOR) pathway. Objective.—To explore the mechanism of loss of B-cell phenotype by correlating expression of B-cell markers with that of Notch1 and downstream targets of the mTOR pathway in plasmablastic lymphoma. Design.—A combination of flow cytometric and immunohistochemical immunophenotyping techniques was used on 9 cases of plasmablastic lymphoma to correlate loss of B-cell markers with expression of Notch1 and downstream activation of the mTOR pathway. These results are compared with 5 cases of primary effusion lymphoma and 21 cases of plasma cell myeloma. Results.—Plasmablastic lymphoma cases exhibit nearly complete loss of B-cell–associated markers and uniform expression of Notch1, with a predominantly nuclear staining pattern. There is a concurrent activation of the mTOR pathway, indicated by expression of mTOR targets eukaryotic initiation factor 4E–binding protein 1 and phosphorylated ribosomal protein S6 in most cases. Similar results are seen in cases of primary effusion lymphoma and plasma cell myeloma. Conclusions.—These findings suggest that activation of Notch1 may be involved in suppression of B-cell–specific gene expression and global loss of the B-cell phenotype in plasmablastic lymphoma, similar to primary effusion lymphoma and plasma cell myeloma. Thus, there might be a role for the Notch1 and mTOR pathways in the pathogenesis and therapy of plasmablastic lymphoma.

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