The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

Arcaini, Luca; Rossi, Davide; Lucioni, Marco; Nicola, Marta Di; Bruscaggin, Alessio; Fiaccadori, Valeria; Riboni, Roberta; Ramponi, Antonio; Ferretti, Virginia Valeria; Cresta, Stefania; Casaluci, Gloria Margiotta; Bonfichi, Maurizio; Gotti, Manuel; Merli, Michele; Maffi, Aldo; Arra, Mariarosa; Varettoni, Marzia; Rattotti, Sara; Morello, Lucia; Guerrera, Maria Luisa; Sciarra, Roberta; Gaïdano, Gianluca; Cazzola, Mario; Paulli, Marco

doi:10.3324/haematol.2014.116855

Cited by 73 publications

(64 citation statements)

References 36 publications

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“…However, NOTCH2 mutation is associated with aggressive behavior in MCL. 10 It is of note that the NOTCH pathway is affected in approximately 25% of cases of LBCL that develop in Hepatitis C virus (HCV)-positive patients, including 20% of NOTCH2 and 4% of NOTCH1, 14 in contrast to the low frequency (1.6%) in HCV-negative patients. Furthermore, the cases with NOTCH mutations were more often associated with the low grade component, and had an adverse prognostic impact.…”

Section: -35mentioning

confidence: 94%

Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

et al. 2017

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Splenic marginal zone lymphoma (SMZL) is a small Bcell lymphoma distinguished by frequent 7q loss and the biased use of IGHV01-02. Massive sequencing techniques have demonstrated NOTCH2 and KLF2 gene mutations to be the most frequent mutations in SMZL, with NOTCH2 mutations occurring in 10-25% of SMZL cases, 1-3 and transcription factor KLF2 mutations present in 12-44% of SMZLs.1,4,5 The clinical impact of NOTCH2 alterations is controversial, with different studies reaching very distinct conclusions.3 Herein, we have analysed NOTCH2 and KLF2 mutations in a large series of SMZLs and examined the associations of these alterations with clinicopathological features. Our results confirm the association of the NOTCH2 mutation with shorter median treatment-free survival and suggest the possible usefulness of the identification of these changes for the diagnosis of SMZL.The study panel comprised a series of 84 SMZL patients, and, for comparison purposes, 76 non-SMZL B-cell lymphomas, including 12 splenic diffuse red pulp B-cell lymphoma (SDRPL), 13 chronic lymphocytic leukemia (CLL), 14 mantle cell lymphoma (MCL), 14 follicular lymphoma (FL), 1 hairy cell leukemia (HCL) and 18 lymphoplasmacytic lymphoma (LPL). Four cases of monoclonal B-cell lymphocytosis (MBL) with non-CLL phenotype were also included. The diagnosis of all the lymphoma types included in the series was performed according to WHO criteria and Matutes et al. 6,7 MBL cases had a B-cell monoclonal population without lymphadenopathy or splenomegaly.The NOTCH2 C-terminal coding exon 34 and the KLF2

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Section: -35mentioning

confidence: 94%

Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

et al. 2017

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“…In this study a comparison was made between HCV-positive and HCV-negative DLBCLs. Mutations of NOTCH2 were found in 20% and of NOTCH1 in 4% of the cases of HCV-positive DLBCL, while only 1/64 HCVnegative cases was found to harbor a NOTCH2 mutation [Arcaini et al 2015]. Interestingly, the presence of these mutations was associated with a shorter overall survival (OS) and with the presence in the diagnostic biopsy of a small cell component that suggests a possible histologic transformation of the DLBCL [Arcaini et al 2015].…”

Section: What Evidence Comes From Epidemiological Studies Linking Nhlmentioning

confidence: 99%

“…Mutations of NOTCH2 were found in 20% and of NOTCH1 in 4% of the cases of HCV-positive DLBCL, while only 1/64 HCVnegative cases was found to harbor a NOTCH2 mutation [Arcaini et al 2015]. Interestingly, the presence of these mutations was associated with a shorter overall survival (OS) and with the presence in the diagnostic biopsy of a small cell component that suggests a possible histologic transformation of the DLBCL [Arcaini et al 2015]. It is already known that NOTCH is a pathway involved in the pathogenesis of SMZL: this finding seems to correlate with the observation that a high proportion of DLBCLs in HCV-positive individuals can arise from a preceding MZL [Besson et al 2006;Michot et al 2015].…”

Section: What Evidence Comes From Epidemiological Studies Linking Nhlmentioning

confidence: 99%

Hepatitis C virus-associated B-cell non-Hodgkin’s lymphomas: what do we know?

Vannata

Arcaini

Zucca

2015

Therapeutic Advances in Hematology

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Abstract:Epidemiological studies have shown an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. There is, however, a great geographic variability and it remains unclear whether additional environmental and genetic factors are involved or whether the international discrepancies represent simply a consequence of the variable prevalence of HCV infection in different countries. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used and the year of publication. The most convincing evidence for a causal relationship comes from the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after successful HCV eradication with antiviral treatment. Yet, the molecular mechanism of HCV-induced lymphomagenesis are mainly hypothetical. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by the chronic viral infection. This review will summarize the current knowledge on HCV-associated lymphomas and their management.

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“…These rare translocations were the tip of the iceberg, as frequent activating NOTCH1 mutations were subsequently discovered in T-ALL [4]. Recently, multiple reports described recurrent although less prevalent gain-of-function NOTCH1 and NOTCH2 mutations in B cell malignancies, including chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and rarely follicular lymphomas (FL) [5–22]. Non-mutational mechanisms of Notch activation may also exist [23,24].…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

Chiang¹,

Radojčić²,

Maillard

2016

Current Opinion in Hematology

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Purpose of review Highlight recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discuss the therapeutic potential of Notch inhibition. Recent findings NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B cell malignancies truncate the C-terminal PEST domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent super-enhancers that underlie oncogenic Notch functions. Summary Notch signaling is a recurrent oncogenic pathway in multiple T and B cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

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The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

Cited by 73 publications

References 36 publications

Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

Hepatitis C virus-associated B-cell non-Hodgkin’s lymphomas: what do we know?

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

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