The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells

Zhang, Jenny; Jima, Dereje D.; Moffitt, Andrea; Liu, Qingquan; Czader, Magdalena; Hsi, Eric D.; Fedoriw, Yuri; Dunphy, Cherie H.; Richards, Kristy L.; Gill, Javed; Sun, Zhen; Love, Cassandra; Scotland, Paula; Lock, Eric F.; Levy, Shawn; Hsu, David S.; Dunson, David B.; Davé, Sandeep S.

doi:10.1182/blood-2013-07-517177

Cited by 208 publications

(209 citation statements)

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“…28 The finding of the L256P MYD88 mutation in one of our mantle cell lymphoma with plasmacytic differentiation is surprising, as these mutations have been investigated in 4100 mantle cell lymphomas and all had been negative and it was also negative in the remaining six cases with monotypic plasma cells in this study. [44][45][46][47][48] In our MYD88-mutated case cyclin D1 was unequivocally positive in plasma cells and cells with Dutcher bodies, and the tumor carried the t(11;14)(q13;q32) supporting the diagnosis of mantle cell lymphoma and excluding the existence of two different tumors. The consideration of this case as a real mantle cell lymphoma, or alternatively as a lymphoplasmacytic lymphoma or marginal zone lymphoma with the t(11;14)(q13;q32) may be debatable.…”

Section: Discussionmentioning

confidence: 99%

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype

et al. 2015

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Mantle cell lymphoma is a mature lymphoid neoplasm characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. SOX11 is a transcription factor commonly overexpressed in these tumors but absent in most other mature B-cell lymphomas whose function is not well understood. Experimental studies have shown that silencing of SOX11 in mantle cell lymphoma cells promotes the shift from a mature B cell into an early plasmacytic differentiation phenotype, suggesting that SOX11 may contribute to tumor development by blocking the B-cell differentiation program. The relationship between SOX11 expression and terminal B-cell differentiation in primary mantle cell lymphoma and its relationship to the plasmacytic differentiation observed in occasional cases is not known. In this study we have investigated the terminal B-cell differentiation phenotype in 60 mantle cell lymphomas, 41 SOX11-positive and 19 SOX11-negative. Monotypic plasma cells and lymphoid cells with plasmacytic differentiation expressing cyclin D1 were observed in 7 (37%) SOX11-negative but in none of 41 SOX11-positive mantle cell lymphomas (Po0.001). Intense cytoplasmic expression of a restricted immunoglobulin light chain was significantly more frequent in SOX11-negative than -positive tumors (58 vs 13%) (P = 0.001). Similarly, BLIMP1 and XBP1 expression was also significantly more frequent in SOX11-negative than in -positive cases (83 vs 34% and 75 vs 11%, respectively) (P = 0.001). However, no differences in the expression of IRF4/MUM1 were observed among these subtypes of mantle cell lymphoma. In conclusion, these results indicate that SOX11-negative mantle cell lymphoma may be a particular subtype of this tumor characterized by more frequent morphological and immunophenotypic terminal B-cell differentiation features that may be facilitated by the absence of SOX11 transcription factor.

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Section: Discussionmentioning

confidence: 99%

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype

et al. 2015

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“…The TRAF3 gene is also significantly mutated in multiple myeloma (Lawrence et al 2014). BIRC3 is mutated in mantle cell lymphoma and GCB DLBCL but not in Burkitt's lymphoma or ABC DLBCL (Zhang et al 2014).…”

Section: B-cell Lymphoma Defining Pathways Point To the Importance Ofmentioning

confidence: 99%

“…For example, DLBCL typically have mutations affecting B-cell receptor signaling or subunits, e.g., CD79A/B, and in histone modifiers like EZH2 and MLL2, PRDM1, TP53, CARD11, and MYD88 (Lenz et al 2008;Davis et al 2010;Mandelbaum et al 2010;Morin et al 2010;Ngo et al 2011;Lohr et al 2012). MYD88 is also recurrently mutated in other B-cell lymphomas like primary central nervous system lymphoma (PCNSL) (Gonzalez-Aguilar et al 2012), and MLL2 and TP53 mutations have been reported for mantle cell lymphoma (MCL) (Zhang et al 2014). The two main human DLBCL subtypes-activated B cell (ABC) and germinal center B cell (GCB)-which can be distinguished based on differential gene expression and prognosis (Alizadeh et al 2000), also have unique recurrent mutations.…”

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confidence: 99%

“…Exome sequencing efforts in human lymphomas have shown that certain mutations are specific for lymphoma subtypes or shared between only a few subtypes (Zhang et al 2014). For example, DLBCL typically have mutations affecting B-cell receptor signaling or subunits, e.g., CD79A/B, and in histone modifiers like EZH2 and MLL2, PRDM1, TP53, CARD11, and MYD88 (Lenz et al 2008;Davis et al 2010;Mandelbaum et al 2010;Morin et al 2010;Ngo et al 2011;Lohr et al 2012).…”

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Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

et al. 2015

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Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B-and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B-and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.

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“…54 Another protein commonly affected in tumorigenesis is p53 and disruption of the p53 pathway is a common event in MCL. TP53 is one of the most frequently mutated genes (14%-20%) in MCL patients [58][59][60] and both TP53 mutations and strong expression of the protein have been correlated to shorter survival 22,59 and high proliferation. 61 In our recent study, we explored the impact of the molecular markers Ki-67, Cyclin D1, SOX11, and p53 to add prognostic power to MIPI using multivariate analysis.…”

Section: Sox11 As a Prognostic Toolmentioning

confidence: 99%

Emerging role of SOX11 in mantle cell lymphoma

Kuci¹,

Nordström²,

Ek³

2015

BLCTT

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During recent years the neural transcription factor SOX11 has been established as an important biomarker for mantle cell lymphoma. SOX11 is both a diagnostic and prognostic antigen, and may potentially be used for treatment selection for younger patients, in relation to protocols including high dose chemotherapy. The molecular pathways involved are still not fully elucidated and, as SOX11 can interact with several co-transcription factors, functional assays need to be carefully designed to pinpoint SOX11-specific function in a defined cellular context. Furthermore, as SOX11 belongs to a large family of homologous proteins, analysis of SOX11 has been limited by the availability of specific antibodies for detection and pull-down. In this review, we discuss the emerging role of SOX11 in mantle cell lymphoma and discuss the potential impact in relation to tumorigenesis, diagnostics, prognostics, and therapy.

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The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells

Cited by 208 publications

References 46 publications

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

Emerging role of SOX11 in mantle cell lymphoma

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