Epstein-Barr virus-induced metabolic rearrangements in human B-cell lymphomas

Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect). More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein-Barr virus (EBV) was the first virus linked with cancer in humans when Burkitt lymphoma (BL) was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas

Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy

Prognostic Markers in Peripheral T-Cell Lymphoma

Based on their own experience and knowledge of the literature, the authors review the pathobiological characteristics of peripheral T-cell lymphomas (PTCLs), focusing on the available prognostic indicators. The International Prognostic Index (IPI), which is based on age, performance status, lactate dehydrogenase [LDH], stage, and extranodal involvement, appears to be efficient as a prognostic index for PTCLs, at least in part and especially for certain PTCL subtypes. However, it is not so satisfactory for the two commonest PTCLs, PTCL not otherwise specified (PTCL/NOS) and angioimmunoblastic T-cell lymphoma (AITL), for which novel scores, possibly based on the biologic features of the tumors, have been explored. An Italian cooperative group proposed a revision of the IPI for PTCL unspecified (PTCL-U), the Prognostic Index for PTCL-U (PIT), which includes age, performance status, LDH, and bone marrow involvement. The PIT apparently offered some advantages, but they were not confirmed in subsequent studies. A clinical-biological score (the Bologna score) was then proposed, including tumor proliferation and clinical features (age, LDH, and performance status). This score appears promising and offers the intriguing advantage of integrating biological and clinical elements, but independent validation on a large series is still warranted. More recently, gene expression profiling has been used to identify novel molecular prognostic factors. In particular, inactivation of the NFκB pathway, high expression of proliferation-associated genes, and cytotoxic molecular phenotype seem to be associated with a worse outcome. So far, however, none of these indicators has been validated in an independent series. Finally, various reports have dealt specifically with the prognostication of NK-derived tumors, including nasal and nasal-type lymphomas. Both the IPI and dedicated models have turned out to be of prognostic relevance for these tumors. In conclusion, although the IPI is somewhat effective for PTCL prognostication, novel scores that are more refined and possibly disease-specific are warranted. The validation process for several models, including clinical-pathological and molecular models, is now ongoing

The alteration of lipid metabolism in burkitt lymphoma identifies a novel marker: adipophilin

Background: Recent evidence suggests that lipid pathway is altered in many human tumours. In Burkitt lymphoma this is reflected by the presence of lipid droplets which are visible in the cytoplasm of neoplastic cells in cytological preparations. These vacuoles are not identifiable in biopsy section as lipids are "lost" during tissue processing. Methods and Results: In this study we investigated the expression of genes involved in lipid metabolism, at both RNA and protein level in Burkitt lymphoma and in other B-cell aggressive lymphoma cases. Gene expression profile indicated a significant over-expression of the adipophilin gene and marked up-regulation of other genes involved in lipid metabolism in Burkitt lymphoma. These findings were confirmed by immunohistochemistry on a series od additional histological samples: 45 out of 47 BL cases showed strong adipophilin expression, while only 3 cases of the 33 of the not-Burkitt lymphoma category showed weak adipophilin expression (p<0.05). Conclusions: Our preliminary results suggest that lipid metabolism is altered in BL, and this leads to the accumulation of lipid vacuoles. These vacuoles may be specifically recognized by a monoclonal antibody against adipophilin, which may therefore be a useful marker for Burkitt lymphoma because of its peculiar expression pattern. Moreover this peptide might represent an interesting candidate for interventional strategies. © 2012 Ambrosio et al

Epstein–Barr Virus-Induced Metabolic Rearrangements in Human B-Cell Lymphomas

Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect). More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein–Barr virus (EBV) was the first virus linked with cancer in humans when Burkitt lymphoma (BL) was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas

Increased angiogenesis seems to correlate with inferior overall survival in myeloid sarcoma patients

Myeloid sarcomas (MS) are tumors composed by myeloid elements and developing outside bone marrow. The prognosis is overall poor, only stem cell transplantation being consistently reposted as a potentially curative approach. In this study we explored whether microvessel density, a biomarker of angiogenesis, might be relevant in MS. We studied 60 MS, 24 acute myeloid leukemia, 5 normal bone marrow samples and 2 cases of extramedullary hemopoiesis in patients without evidence of hematological malignancy. We used immunohistochemistry (anti-CD34) to identify and quantify micro-vessel density (MVD) and micro-vessel grading (MVG). We found that MS had significantly higher MVD and MVG than normal bone marrow (p = 0.0002 and p < 0.001, respectively). We then found that cases with monocytic morphology had significantly higher MVD than myelo-monocytic and blastic ones (p = 0.005), while no differences were recorded based on extramedullary site. Finally, we found that higher MVD and higher MVG were associated with inferior outcome in terms of overall survival in multivariate analysis (p = 0.05 and p = 0.02, respectively), when censoring for stem cell transplantation was undertaken. In conclusion, we documented for the first time that increased angiogenesis is characteristic of MS and correlates with survival, suggesting that anti-angiogenic approaches might deserve a clinical evaluation in this setting

Signaling Pathways in Rare Lymphomas

Here we give an overview of select signaling pathways understood or thought to play a key role in the pathogenesis of lymphomas, covering examples of both B-cell and T-cell lymphomas. The selection focuses on providing well-understood examples and may serve as a guideline also for entities not covered in these sections. Remarkably many of these cancers are characterized by genetic alterations that lead to activation of the NF-\u3baB and JAK/STAT pathways. A striking example is seen in MALT lymphoma where recurrent chromosomal translocations targeting different regulatory nodes lead to NF-\u3baB activation. We discuss these mechanisms as well as more disease-specific alterations such as oncogenic activation of MYC in Burkitt\u2019s lymphoma, of TAX in adult T-cell leukemia/lymphoma, of ALK in peripheral T-cell lymphoma, and the MyD88 L265P mutation in Waldenstr\uf6m\u2019s macroglobulinemia. DNA damage pathways are equally of importance and discussed in the context of with mantle cell lymphoma and Burkitt\u2019s lymphoma. A striking example of how dysregulation of immune surveillance pathways interfaces with activation of oncogenic pathways is seen in the case of primary mediastinal B-cell lymphom

The cell of origin of Burkitt lymphoma: Germinal centre or not germinal centre?

We read with interest the \u2018Accepted article\u2019 in Histopathology of Park and colleagues1 that reports novel insight into the early histopathogenesis of immunodeficiency\u2010associated Burkitt lymphoma (BL), suggesting a possible relationship with monocytoid B cell and speculating on the BL cell of origin. In addition, the paper raises the question of the polymicrobial nature of BL, as cytomegalovirus (CMV) was also detected