The Germinal centre-derived lymphomas seen through their cellular microenvironment

The human lymph node is a complex tissue resulting from the microenvironmental organisation of different cell populations linked by topographical and/or functional relationships. Germinal centres (GCs) of lymphoid follicles contain a meshwork of follicular dendritic cells in addition to B-cells and some CD4⁺ T cells. Moreover, there is a sharp demarcation around the whole follicle centre, which is highlighted by fibroblastic reticulum cells. On the whole, GC exerts a role in B cell physiology and malignancy. In GC-derived lymphomas, gene expression profiling studies have raised the possibility that survival of the affected patients may be associated with signatures preferentially expressed in non-malignant T cells and macrophages and/or dendritic cells. Immunohistological analyses in lymphoma biopsy samples have confirmed that the biological behaviour and tumour progression may be influenced by the tumour microenvironment. This review will examine GC-derived lymphomas, including follicular lymphomas, Hodgkin lymphomas and angioimmunoblastic T-cell lymphoma, through their integrated cellular microenvironment, highlighting those findings which may serve as a useful surrogate marker for tumour diagnosis or tumour progression, together with key molecules involved in tumour development.     

Novel therapies targeting cutaneous T cell lymphomas and their microenvironment

Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas with a generally indolent course managed with topical, skin-directed therapies. A small subset, however, will progress to advanced stage disease necessitating systemic therapy for disease control. Currently approved therapies have low response rates and generally short durations of response. Novel therapies, therefore, are urgently needed to address this unmet need. In this review, the mechanisms of CTCL pathogenesis and progression, including the role of the tumor microenvironment and molecular alterations, are summarized. Based on these biologic insights, novel therapies currently under investigation and those with a strong preclinical biologic rationale including T cell and macrophage checkpoint inhibitors, epigenetic regulators, targeted antibodies, tyrosine kinase inhibitors, and apoptosis modulating therapies are discussed.     

Relationships between lymphomas linked to hepatitis C virus infection and their microenvironment

The relationships between lymphomas and their microenvironment appear to follow 3 major patterns:(1)an independent pattern;(2)a dependent pattern on deregulated interactions;and(3)a dependent pattern on regulated coexistence.Typical examples of the third pattern are hepatitis C virus(HCV)-associated marginal zone lymphomas(MZLs)and mucosa-associated lymphoid tissue lymphomas.In these lymphomas,a regulated coexistence of the malignant cells and the microenvironmental factors usually occurs.At least initially,however,tumor development and cell growth largely depend on external signals from the microenvironment,such as viral antigens,cytokines,and cell-cell interactions.The association between HCV infection and B-cell lymphomas is not completely defined,although this association has been demonstrated by epidemiological studies.MZL and diffuse large B-cell lymphoma are the histotypes most frequently associated with HCV infection.Many mechanisms have been proposed for explaining HCV-induced lymphomagenesis;antigenic stimulation by HCV seems to be fundamental in establishing B-cell expansion as observed in mixed cryoglobulinemia and in B-cell lymphomas.Recently,antiviral treatment has been proved to be effective in the treatment of HCV-associated indolent lymphomas.Importantly,clinically responses were linked to the eradication of the HCV-RNA,providing a strong argument in favor of a causative link between HCV and lymphoproliferation.     

Early stages in the ontogeny of small B‐cell lymphomas: genetics and microenvironment

In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B‐cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin‐variable domains can indicate a role for stimulants of the B‐cell receptor before, during and after malignant transformation. The pathways driven via the B‐cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.     

Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase

The c-Jun N-terminal kinase (JNK), or stress-activated protein kinase plays a crucial role in cellular responses stimulated by environmental stress and proinflammatory cytokines. However, the mechanisms that lead to the activation of the JNK pathway have not been elucidated. We have isolated a cDNA encoding a novel protein kinase that has significant sequence similarities to human germinal center kinase (GCK) and human hematopoietic progenitor kinase 1. The novel GCK-like kinase (GLK) has a nucleotide sequence that encodes an ORF of 885 amino acids with 11 kinase subdomains. Endogenous GLK could be activated by UV radiation and proinflammatory cytokine tumor necrosis factor α. When transiently expressed in 293 cells, GLK specifically activated the JNK, but not the p42/44^MAPK/extracellular signal-regulated kinase or p38 kinase signaling pathways. Interestingly, deletion of amino acids 353–835 in the putative C-terminal regulatory region, or mutation of Lys-35 in the putative ATP-binding domain, markedly reduced the ability of GLK to activate JNK. This result indicates that both kinase activity and the C-terminal region of GLK are required for maximal activation of JNK. Furthermore, GLK-induced JNK activation could be inhibited by a dominant-negative mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1) or mitogen-activated protein kinase kinase 4/SAPK/ERK kinase 1 (SEK1), suggesting that GLK may function upstream of MEKK1 in the JNK signaling pathway.     

Gamma‐delta t‐cell lymphomas

Gamma‐delta T‐cell lymphomas are aggressive and rare diseases originating from gamma‐delta lymphocytes. These cells, which naturally play a role in the innate, non‐specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma‐delta T‐cell lymphoma (HSGDTL) and primary cutaneous gamma‐delta T‐cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long‐term survival is anecdotal. Available literature on gamma‐delta T‐cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma‐delta T‐cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies.     

Regulation of bone mass through pineal‐derived melatonin‐MT2 receptor pathway

Tryptophan, an essential amino acid through a series of enzymatic reactions gives rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological functions. We show here that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal‐derived neurohormone. Pineal gland‐specific deletion of Tph1, the enzyme that catalyzes the first step in the melatonin biosynthesis lead to a decrease in melatonin levels and a low bone mass due to an isolated decrease in bone formation while bone resorption parameters remained unaffected. Skeletal analysis of the mice deficient in MT1 or MT2 melatonin receptors showed a low bone mass in MT2?/? mice while MT1?/? mice had a normal bone mass compared to the WT mice. This low bone mass in the MT2?/? mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the MT1?/? and MT2?/? mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of MT2?/? osteoblasts compared to WT counterparts, and the mutant cells did not respond to melatonin addition. Finally, we demonstrate that daily oral administration of melatonin can increase bone accrual during growth and can cure ovariectomy‐induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal‐derived melatonin as a regulator of bone mass through MT2 receptors, this study expands the role played by tryptophan derivatives in the regulation of bone mass and underscores its therapeutic relevance in postmenopausal osteoporosis.     

Acquired immunodeficiency syndrome-associated lymphomas are efficiently lysed through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by rituximab

Rituximab (Mabthera) and alemtuzumab (Campath(R), Mabcampath(R)) are non-conjugated IgG1 therapeutic monoclonal antibodies directed against the CD20 and CD52 surface antigens respectively. They are presently used in the therapy of indolent B-cell non-Hodgkin's lymphoma (B-NHL) and of B-cell chronic lymphocytic leukaemia, and are thought to act mainly through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Here we have analysed the capacity of these two monoclonal antibodies to lyse cell lines of acquired immunodeficiency syndrome (AIDS)-related B-NHL through either complement activation or antibody-dependent cytotoxicity. Rituximab strongly activated both CDC and ADCC against CD20-positive AIDS-NHL cells lines, inducing up to 60-98% and 20% specific lysis respectively. In contrast, alemtuzumab was a poor activator of CDC, even in the AIDS-NHL cell lines expressing high amounts of CD52, leading to a lysis of only 1-30%, whereas it was at least as strong as rituximab in inducing ADCC of the same lines (up to 30% specific lysis). Altogether, these data offer a first in vitro rationale supporting the therapeutic use of rituximab for CD20-positive AIDS-NHL.     

Endothelial precursor cells stimulate pericyte‐like coverage of bone marrow‐derived mesenchymal stem cells through platelet‐derived growth factor‐BB induction,which is enhanced by substance P

Objective

The aim of this study was to evaluate the angiogenicity of a combination of BM‐EPCs and BM‐MSCs in vitro in the presence of SP and its working mechanism.

Methods

BM‐MSCs and BM‐EPCs were cocultured with or without SP. ELISA and RT‐PCR were performed to detect angiogenic factors such as VEGF and PDGF‐BB. N‐cadherin was detected by Western blot analysis. The tubular network‐forming ability was evaluated by a Matrigel tube‐forming assay.

Results

BM‐EPCs coculture with BM‐MSCs strongly stimulated the recruitment of BM‐MSCs onto the BM‐EPC‐generated endothelial tubular network. Upon SP treatment, endothelial branching point, tubule length, and tubular recruitment of BM‐MSCs were further increased and stabilized. The coculture of BM‐EPCs and BM‐MSCs synergistically stimulated expression of VEGF, VEGF receptor, N‐cadherin, and PDGF‐BB, all of which were further enhanced by SP treatment. Blockade of PDGF‐BB by its functional blocking antibodies markedly reduced the BM‐MSC incorporation into the endothelial tubules. SP‐pretreated BM‐MSCs were preferentially incorporated into the preformed BM‐EPC tubular network.

Conclusions

BM‐EPCs along with SP promote the pericyte‐like coverage of BM‐MSCs on endothelial tubules possibly through the induction of PDGF‐BB.     

Apheresis platelet concentrates contain platelet‐derived and endothelial cell‐derived microparticles

Background and Objectives Microparticles (MP) are membrane vesicles with thrombogenic and immunomodulatory properties. We determined MP subgroups from resting platelets, activated platelets and endothelial cells in donors and apheresis platelet concentrates (PC). Material and Methods MP were double stained with annexin V and CD61 (platelet‐derived MP; PMP), P‐selectin or CD63 (MP from activated platelets) and CD144 plus E‐selectin (endothelial cell‐derived MP; EMP) and detected by flow cytometry in platelet donors (n = 36) and apheresis PC (n = 11; Trima?). Results PC contained MP, mainly from resting platelets [93% (90–95)], and minor fractions of PMP from activated platelets [P‐selectin⁺ or CD63⁺; 4·8% (3·2–7·7) and 2·6% (2·0–4·0)]. Compared to donors, levels of annexin V+ MP, PMP, P‐selectin⁺ and CD63⁺ MP were 1·7‐, 2·3‐, 8·6‐ and 3·1‐fold higher in PC (all P < 0·05). During storage (1–5 days), levels of annexin V+ MP and PMP did not increase, although small increases in the fraction of P‐selectin⁺ or CD63⁺ MP occurred (both P < 0·05). PC also contained EMP, which were 2·6‐ to 3·7‐fold enriched in PC compared to donors (P < 0·05). Conclusions Transfusion of apheresis PC also results in transfusion of HLA‐carrying PMP and EMP. This might counteract the aim of reducing transfused HLA load by leucodepletion. The increases in PMP exposing P‐selectin or CD63 reflect mild platelet activation during storage. We conclude that in leucodepleted platelet apheresis using fluidized particle bed technology, MP are harvested mainly from the donor by apheresis. Improvement in apheresis technology might reduce MP load.     

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first‐degree relatives

Objective

Patients with rheumatoid arthritis (RA) are at increased risk for malignant lymphomas. Both conditions display a familial aggregation, and there are reports of RA and malignant lymphomas occurring in the same families. This study was undertaken to determine the risk of malignant lymphomas in first‐degree relatives of RA patients, in order to investigate whether the increased risk of malignant lymphomas in RA could be due to genetic or environmental risk factors common to both conditions, rather than being a consequence of the rheumatic disease.

Methods

Using Swedish nationwide and population‐based registers, we identified 76,527 patients hospitalized with RA in 1964–1999 and 70,290 first‐degree relatives of a subset of these patients. These subjects were followed up for more than 3 decades, and information on cancer occurrence was recorded.

Results

Patients with RA had a significantly increased risk of malignant lymphomas (535 cases; standardized incidence ratio [SIR] 2.00, 95% confidence interval [95% CI] 1.83–2.17), which was apparent for up to 2 decades of followup. Among the first‐degree relatives without RA, no increased risk of malignant lymphomas was found overall, although modest and nonsignificantly elevated risk estimates were observed in subgroups. With respect to childhood cancer (0–14 years of age), we observed an increased risk of Hodgkin's lymphoma (5 cases; SIR 3.18, 95% CI 1.03–7.42).

Conclusion

Patients with RA are at a markedly, but possibly time‐limited, increased risk for malignant lymphomas. There is little to suggest a prominent role for coinherited or common environmental risk factors in malignant lymphomas arising in the context of RA. Instead, lymphomas complicating RA appear to be a direct consequence of the inflammation or its treatment.

     

Treatment options for primary splenic low‐grade non‐Hodgkin's lymphomas

The purpose of this comparative study was to evaluate the response of primary splenic low‐grade non‐Hodgkin's lymphomas (NHL) to chemotherapy, splenectomy, and chemotherapy combined with splenectomy in order to elaborate the optimum treatment modality. A total of 104 patients (age range: 15–82 years) with primary low‐grade B‐cell NHL of the spleen were comprised by our study. Stage IV disease was determined in 102 (98.1%) cases. Regarding the treatment modality, splenectomy was performed in 14 patients, early splenectomy and single‐agent chemotherapy in 15, early splenectomy and combined chemotherapy in 19, single‐agent chemotherapy in 23, and combined chemotherapy in 33. In the above‐mentioned order, complete remission rate was following: none, 40.0, 31.6, 21.8, and 18.2%. Partial remissions were achieved in 85.7, 46.7, 57.9, 30.4, and 69.7% of cases, respectively. The median remission duration turned out to be longer (74.5 months) in the group of patients with complete remissions attained by means of splenectomy and combined chemotherapy. Local relapses in the spleen developed in 19 (72.7%) patients treated with combined chemotherapy and in 9 (90.0%), who had undergone single‐agent chemotherapy. The 5‐year overall survival was 54.4% after splenectomy, 39.4% after single‐agent chemotherapy, and 37.1% after combined chemotherapy, being significantly higher (P < 0.05) after splenectomy and single‐agent chemotherapy (67.2%), and splenectomy followed by combined chemotherapy (64.7%). Early splenectomy combined with chemotherapy is the optimum treatment option for primary low‐grade NHL of the spleen because of the superiority in complete remission rate, remission duration, and in overall survival rate. Splenectomy leads to somatic compensation of patients, makes impossible local relapsing in the spleen, prevents continuous dissemination from the primary tumor site, and mostly corrects cytopenias, creating better conditions for chemotherapy.     

The aggressive peripheral T‐cell lymphomas: 2015

Background: T‐cell lymphomas make up approximately 10%–15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. Diagnosis: The diagnosis of aggressive peripheral T‐cell lymphoma (PTCL) is usually made using the World Health Organization classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than that for aggressive B‐cell lymphomas, with a range of 72%–97% for the aggressive PTCLs. Risk Stratification: Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography scans seem to be useful as they are in aggressive B‐cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large‐cell lymphoma—particularly young patients with the anaplastic lymphoma kinase positive subtype. Risk‐Adapted Therapy: Anaplastic large‐cell lymphoma is the only subgroup to have a good response to a CHOP‐like regimen. Angioimmunoblastic T‐cell lymphoma has a prolonged disease‐free survival in only ～20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL‐not otherwise specified is not one disease. Anthracycline‐containing regimens have disappointing results, and a new approach is needed. Natural killer/T‐cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy‐containing regimens. Enteropathy‐associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy‐associated PTCL seem to benefit from intensive therapy. Am. J. Hematol. 90:666–673, 2015. © 2015 Wiley Periodicals, Inc.