The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma

Ruminy, Philippe; Étancelin, Pascaline; Couronné, Lucile; Parmentier, Françoise; Rainville, Vinciane; Mareschal, Sylvain; Bohers, Élodie; Burgot, Celine; Cornic, Marie; Bertrand, Philìppe; Lenormand, Bernard; Picquenot, Jean‐Michel; Jardin, Fabrice; Tilly, Hervé; Bastard, Christian

doi:10.1038/leu.2010.302

Cited by 69 publications

(57 citation statements)

References 29 publications

(34 reference statements)

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“…1C). This finding is consistent with previous work demonstrating that ABC but not GCB DLBCL tumors have genetic lesions that disrupt the switch μ region of the IgH locus that is necessary for Ig class-switch recombination (19,24). Of note, the frequency of IgM BCRs among V H 4-34 + ABC samples was nearly 90%, which was higher than in V H 3-7 + samples (77%) and in all other ABC samples (75%) (Fig.…”

Section: Resultssupporting

confidence: 81%

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Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Young

Schmitz

et al. 2015

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

154

156

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one V H 4-34 + ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of V H 4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.lymphoma | cancer biology | B-cell receptor

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Section: Resultssupporting

confidence: 81%

“…1A). Previous studies also found an enrichment for V H 4-34 in limited sets of DLBCL (18) or non-GCB DLBCL cases (19,20). Besides V H 4-34, the only IgV H that was more prevalent in ABC DLBCL than in GCB DLBCL and normal B cells was V H 3-7, which was expressed in 7.8% of ABC DLBCL cases (Fig.…”

Section: Resultsmentioning

confidence: 90%

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Young

Schmitz

et al. 2015

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

154

156

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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: 68%

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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“…The GCB/ABC signature was determined by DASL technology with RNA extracted from fresh frozen material as previously reported. 5,6 By this reproducible and robust method, we observed a concordance rate of 70-95% with immunohistochemistry. 5,6 A direct comparison with microarray-based technology using RNA extracted from formalin-fixed paraffin-embedded tissues is ongoing.…”

mentioning

confidence: 80%

“…9 We have previously shown that VH4-34 + DLBCL frequently expressed IgM, frequently displayed the t(3;14)(q27;q32) translocation, and are typically classified in the ABC subtype. 5,10 This suggests that the increase in the proportion of ABC DLBLC with age may reflect a change in the B-cell population during aging. Another hypothesis relates to the putative pathological specificity of DLBCL occurring in elderly patients.…”

mentioning

confidence: 99%

The proportion of activated B-cell like subtype among de novo diffuse large B-cell lymphoma increases with age

Mareschal¹,

Lanic²,

Ruminy³

et al. 2011

Haematologica

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The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma

Cited by 69 publications

References 29 publications

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

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

The proportion of activated B-cell like subtype among de novo diffuse large B-cell lymphoma increases with age

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