Clinicopathologic Characterization of Diffuse-Large-B-Cell Lymphoma with an Associated Serum Monoclonal IgM Component

Cox, Maria Christina; Napoli, Arianna Di; Scarpino, Stefania; Salerno, Gerardo; Tatarelli, Caterina; Talerico, Caterina; Lombardi, Mariangela; Monarca, Bruno; Amadori, Sergio; Ruco, Luigi

doi:10.1371/journal.pone.0093903

Cited by 38 publications

(49 citation statements)

References 53 publications

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“…Reduction of AICDA transcripts would predict a reduction in somatic hypermutation (SHM). Consistent with this hypothesis, BCRs expressed by primary ABC-DLBCLs often are minimally mutated (37)(38)(39), and transgenic FOXP1-overexpressing mice show GCB cell deficiency (34). Other notable GCB cell identity genes directly repressed after FOXP1 KD include (i) IRF8, which is highly expressed in normal GCB and GCB-DLBCL (40) and negatively regulates PC differentiation (41); (ii) GAB1, an adapter that recruits SH2 domain-containing proteins to the ligated BCR (42); and (iii) LRMP, a lymphoid-restricted membrane protein involved in Ag receptor assembly (43) whose overexpression is a GCB-DLBCL classifier (2,43).…”

Section: Foxp1 Directly Represses Gene Signatures Associated With Gcbmentioning

confidence: 81%

Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

Dekker

Park

Shaffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB cell to the plasmablast-the transient B-cell stage targeted in ABC-DLBCL transformation-by antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB "master regulator," BCL6 (B-cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical subtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.iffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, striking ∼69,000 new patients annually in the United States (1). Although previously diagnosed and treated uniformly based on morphology and surface markers (2, 3), gene expression profiling (GEP) defined two major subtypes corresponding to the suspected B cell of origin (2, 3): the germinal center (GC) B cell for GCB-DLBCL (2) and the activated B cell (ABC) plasmablast (PB) for ABC-DLBCL (2). PBs exist transiently before terminal commitment to plasma cells (PC) and are proposed to be targeted for transformation in ABC-DLBCL (2, 4).A hallmark of ABC-DLBCL is constitutive activation of the classical NF-κB pathway (4, 5). Activation of IKKβ and NF-κB signaling downstream of the B-cell receptor (BCR) (6) depends on the CBM complex, a signaling hub that includes CARD11, BCL10, and MALT1 (4). Roughly 10% of ABC-DLBCLs have CARD11 mutations (6). Another ∼10% harbor activating mutations in BCR components, including signal-transducing subunits CD79A and CD79B (6, 7). ABC-DLBCLs associated with chronic activation of BCR signaling (CABS) are specifically killed by shRNA targeting CBM components (4, 7). Another major route to NF-κB activation in ABC-DLBCL is via MYD88 (myeloid differentiation primary response gene 88), an adaptor protein whose mutation in ∼40% of ABC-DLBCL cases (8) up-regulates gene expression signatures of NF-κB, JAK-STAT, and type I IFN signaling (8).Current multiagent chemotherapy achieves ∼80% 3-y survival for GCB-DLBCL, but only 45% for patients with ABC-DLBCL (1), and most ABC-DLBCL patients relapse with refractory disease (3, 9). GEP revealed genes associated with the length of survival (10). These "classifier" genes reflected biological features of the tumors that influenced the efficacy of chemotherapy (11). One such classifi...

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Section: Foxp1 Directly Represses Gene Signatures Associated With Gcbmentioning

confidence: 81%

Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

Dekker

Park

Shaffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent study characterized DLBCL associated with the presence of a serum IgM monoclonal gammopathy, so-called "IgM-secreting DLBCL." 27 It was present in 12.5% of all patients with DLBCL, is almost exclusively non-GCB, and defines a subset with a very poor prognosis. 27 Notable was a high frequency of .…”

mentioning

confidence: 99%

“…27 It was present in 12.5% of all patients with DLBCL, is almost exclusively non-GCB, and defines a subset with a very poor prognosis. 27 Notable was a high frequency of .…”

mentioning

confidence: 99%

Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL

Savage¹,

Slack

Mottok

et al. 2016

Blood

161

112

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Key Points• Dual expression of MYC and BCL2 is associated with an increased risk of CNS relapse in DLBCL treated with R-CHOP.Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalinfixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNSInternational Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P 5 .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC 1 BCL2 1 DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies. (Blood. 2016;127(18):2182-2188

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“…There is also documented evidence of DLBCL with paraproteinemia due to clonal plasma cell proliferation [5]. However, demonstration of both DLBCL with malignant non-secretory plasma cells in the bone marrow in adjacent marrow spaces is unique and has not been reported in literature.…”

Section: Discussionmentioning

confidence: 99%

“…Prognosis of this entity should be studied further, as DLBCL with paraproteinemias as well as DLBCL with plasmablastic differentiation has a poor prognosis and is a therapeutic challenge. [4,5].…”

Section: Discussionmentioning

confidence: 99%

Synchronous Diffuse Large B-Cell Lymphoma and Malignant Clonal Plasma Cells in Bone Marrow As Primary Presentation: A Diagnostic and Therapeutic Challenge

Sachdev

Goel

Gajendra

et al. 2015

JCDR

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Clinicopathologic Characterization of Diffuse-Large-B-Cell Lymphoma with an Associated Serum Monoclonal IgM Component

Cited by 38 publications

References 53 publications

Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL

Synchronous Diffuse Large B-Cell Lymphoma and Malignant Clonal Plasma Cells in Bone Marrow As Primary Presentation: A Diagnostic and Therapeutic Challenge

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