Natural Killer Cell Lymphoproliferative Diseases Research Articles

CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor (GPCR) for CCL22, CCR4, via impaired β-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a unique mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased GPCR signaling and dysregulation of microenvironmental crosstalk.

From pathobiology to targeted treatment in Epstein Barr virus related T cell and Natural Killer cell lymphoproliferative diseases

: Epstein Barr virus (EBV), a gamma-1 herpesvirus, establishes a life-long latent infection in the majority of individuals worldwide. Whilst this seemingly innocuous virus is carried as an asymptomatic infection of memory B cells, EBV is paradoxically linked to two pre-malignant lymphoproliferative diseases (LPDs) and up to nine aetiologically distinct human tumours, accounting for up to 200,000 cancers per year. Although these malignancies primarily occur in B cells and epithelial cells, correlating with the natural tropism of the virus, on rare occasions EBV also infects T and NK cells leading to various pre-malignant LPDs, lymphomas and leukaemia. These conditions are often highly aggressive and are associated with hyperinflammation and organ dysfunction leading to substantial mortality. While, in recent years improvements in chemotherapy, especially asparaginase based regimens, have led to improved outcomes for some, these conditions are often intrinsically chemoresistant with allograft often providing the only curative option. In this review, we address the impact of genetic and epigenetic changes on the pathogenesis of the T/NK cell LPDs and bring together an analysis of recent clinical trials attempting to target these processes. We describe the main molecular characteristics across the range of EBV-associated T/NK cell diseases, from somatic mutations effecting epigenetic regulators seen across EBV related T/NK LPD subtypes to the marked dysregulation of the JAK-STAT-MYC axis observed in higher grade disease such as extranodal NK/T lymphoma (ENKTL). We then go on to analyse the novel therapeutic options available including immunomodulation and small molecule inhibitors. While these approaches show promise in early phase trials there is still much scope for improvement and a need to better understand the pathophysiology to design rational combination treatments.

Acute Epstein‐Barr virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Acute <scp>Epstein‐Barr</scp> virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Multiple small tumor formation on both surfaces of the aortic valve cusps in Epstein\u2013Barr virus-associated T/NK-cell lymphoproliferative disease: a case report

A 41-year-old woman presented acute cerebral infarction. Transesophageal echocardiography revealed multiple masses only on both surfaces of the aortic valve cusps. There was no primary lesion outside the heart according to various examinations. After treatment for cerebral infarction, we replaced the aortic valve instead of preservation because the intraoperative histological examination reported that malignancy was highly suspected. Contrary to the rapid frozen section diagnosis, histological and immunohistochemical examinations failed to exhibit malignancy. The tumors were composed of atypical large lymphoid cells and they were assessed to be related to T-/natural killer-cells. Furthermore, Epstein–Barr virus related markers were also positive. Her three-year postoperative course was uneventful without chemotherapy. We report an extremely rare case of Epstein–Barr virus-associated T-/natural killer-cell lymphoproliferative disease which formed multiple small tumors on both surfaces of the aortic valve.

Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases.

The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning "LPAM140 regimen," which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210mg/m2 ("LPAM210 regimen"). Patient data (n=22; LPAM140, n=7; LPAM210, n=15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P=.002). Fludarabine combined with melphalan (210mg/m2 ) had a favorable impact on engraftment.

Cytologic Analysis of Epstein-Barr Virus-Associated T/Natural Killer-Cell Lymphoproliferative Diseases.

Rapid, precise diagnosis of Epstein-Barr virus-associated T lymphocyte or natural killer cell lymphoproliferative diseases is clinically important to prevent disease progression and avoid fatal outcomes for patients. In addition to detecting increased copy numbers of Epstein-Barr virus, identification of the lymphocyte subpopulation targeted by the virus infection is crucial to reaching the final diagnosis. However, these procedures are laborious and require large amounts of sample. In contrast, flowcytometric analysis may provide crucial information for initial screening of diseases using only small amounts of sample and involves little labor. In addition to the increase of a particular subpopulation, selective HLA-DR expression indicates selective activation and expansion of a virus-infected clone. Presence of a characteristic HLA-DRhigh CD5dim/negative fraction within CD8+ T lymphocytes indicates a possible diagnosis of Epstein-Barr virus-associateds hemophagocytic lymphohistiocytosis. One should note, however, that cases with familial hemophagocytic lymphohistiocytosis may exhibit a similar abnormal fraction within CD8+ T lymphocytes. These T cells are oligoclonally expanded reactive T cells expanding in response to B cells infected with Epstein-Barr virus.

Modeling EBV infection and pathogenesis in new-generation humanized mice.

The development of highly immunodeficient mouse strains has allowed the reconstitution of functional human immune system components in mice. New-generation humanized mice generated in this manner have been extensively used for modeling viral infections that are exclusively human tropic. Epstein–Barr virus (EBV)-infected humanized mice reproduce cardinal features of EBV-associated B-cell lymphoproliferative disease and EBV-associated hemophagocytic lymphohistiocytosis (HLH). Erosive arthritis morphologically resembling rheumatoid arthritis (RA) has also been recapitulated in these mice. Low-dose EBV infection of humanized mice results in asymptomatic, persistent infection. Innate immune responses involving natural killer cells, EBV-specific adaptive T-cell responses restricted by human major histocompatibility and EBV-specific antibody responses are also elicited in humanized mice. EBV-associated T-/natural killer cell lymphoproliferative disease, by contrast, can be reproduced in a distinct mouse xenograft model. In this review, recent findings on the recapitulation of human EBV infection and pathogenesis in these mouse models, as well as their application to preclinical studies of experimental anti-EBV therapies, are described.

Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma

Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma Makoto Yoshimitsu, Naomichi Arima Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan Abstract: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by latent infection of human T-cell lymphotropic virus type 1. The outcome for ATLL is very poor, with a 3-year overall survival of approximately 24% with conventional chemotherapy; thus, there is an unmet need for developing new treatment options. Defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody (KW-0761, mogamulizumab) has been clinically available for the treatment of relapsed or refractory ATLL in Japan since 2012, and a Phase II study of mogamulizumab for patients with relapsed CCR4+ ATLL demonstrated a 50% objective response, a 30.8% complete response, and an acceptable safety profile. Allogeneic hematopoietic stem cell transplantation has been used to treat patients with ATLL, and mogamulizumab in combination with allogeneic hematopoietic stem cell transplantation has been used successfully in a limited number of patients to treat refractory or relapsed ATLL. The efficacy of combining mogamulizumab with standard chemotherapy (mLSG15) for patients with ATLL has also been examined, and the results have shown higher rates of complete response with the combined therapy (52%) compared with for chemotherapy alone (33%). Mogamulizumab also has potential application in the treatment of human T-cell lymphotropic virus type 1-associated myelopathy/tropical paraparesis, Epstein&ndash;Barr virus-associated T-cell and natural killer-cell lymphoproliferative diseases, and peripheral and cutaneous T-cell lymphomas. Possible adverse events of mogamulizumab have been reported, such as cutaneous adverse reactions (including Stevens&ndash;Johnson syndrome), diffuse panbronchiolitis, reactivation of hepatitis B, and opportunistic infections. The treatment outcome of patients with ATLL might be improved by further optimizing the use of mogamulizumab and managing severe adverse events. In this review, we provide an overview of the current treatment options for patients with ATLL and a focused review on the use, application, and adverse events associated with mogamulizumab. Keywords: ATLL, anti-CCR4 antibody, defucosylated antibody, cutaneous adverse reaction

Highlights of This Issue

The correlation between tumor cell PD-L1 expression in pretreatment surgical pathology specimens and response to anti-PD-1 therapy is an exciting, but preliminary finding. Taube and colleagues expand upon their earlier observations to assess additional histologic and immunoarchitectural features of the pretreatment tumor microenvironment and how they correlate with response to anti-PD1. The presence of immune infiltrates, immune cell subsets, and PD-1, PD-L1 and PD-L2 expression were assessed by immunohistochemistry. Of these, tumor cell PD-L1 expression was the single factor most closely associated with objective response. These findings have both mechanistic and potential biomarker relevance for anti-PD-1 therapy.XAGE1 (GAGED2a) is a cancer/testis (CT) antigen expressed frequently in lung adenocarcinoma, which is the predominant histologic type of lung cancer. Ohue and colleagues investigated the clinical relevance of the XAGE1 (GAGED2a) immune responses in advanced lung adenocarcinoma patients and found that the XAGE1 (GAGED2a) immune response is relevant for better prognosis and that the XAGE1 (GAGED2a) antibody response is a prognostic immune biomarker. On the other hand, XAGE1 (GAGED2a) antigen expression is predictive of a worse prognosis in patients with EGFR-mutated tumors. The protective effect of this naturally occurring immune response supports the concept of immunotherapy.Epstein-Barr virus (EBV) occasionally leads to T- and natural killer-cell lymphoproliferative diseases (T/NK-LPDs) that are refractory to conventional chemotherapies. Kanazawa and colleagues identified that CC chemokine receptor 4 (CCR4) was expressed on most EBV-positive T- and NK-cell lines. A humanized anti-CCR4 monoclonal antibody, mogamulizumab induced antibody-dependent cellular cytotoxicity activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. These finding suggests that mogamulizumab may be a promising therapeutic for patients with EBV-associated T/NK-LPDs.STAT3 is activated in many forms of cancer. Because PIAS3 is a key endogenous inhibitor of STAT3, it is possible that PIAS3 expression could be decreased in malignant tissue and thereby contribute to high STAT3 activation. Indeed, Dabir and colleagues demonstrated this was true in malignant mesothelioma as PIAS3 transcript levels were among the lowest of all solid tumors and, conversely, high expression of PIAS3 in mesothelioma tumors is predictive of a favorable prognosis. The authors went on to demonstrate that increasing PIAS3 expression in STAT3-driven mesothelioma cells, either by overexpression of exogenous PIAS3, stimulation of endogenous PIAS3 expression by curcumin or incubation with a PIAS3 peptide mimetic, led to decreased cellular STAT3 activation and promoted apoptosis. These results suggest that strategies to reactivate PIAS3 could represent a new therapeutic avenue to inhibit STAT3 activity and induce growth arrest in tumor cells.

Umbilical Cord Blood as an Alternative Source of Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Epstein-Barr Virus–Associated T or Natural Killer Cell Lymphoproliferative Diseases

Chronic Epstein-Barr virus–associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor.

Application of flow cytometric in situ hybridization assay to Epstein–Barr virus‐associated T/natural killer cell lymphoproliferative diseases

Epstein-Barr virus (EBV) infects various types of lymphocytes and is associated with not only B cell-origin lymphoma, but also T or natural killer cell lymphoproliferative diseases (T/NK LPD). Recently, we established a novel assay to identify EBV-infected cells using FISH. Using this assay, dual staining with antibodies to both surface antigens and an EBV-encoded small RNA (EBER) probe can be performed. In the present study, we applied this recently developed FISH assay to EBV-associated T/NK LPD to confirm its diagnostic utility. Using FISH, we prospectively analyzed peripheral blood from patients with suspected EBV-associated T/NK LPD. The results were compared with those obtained using immunobead sorting followed by quantitative PCR. In all, 26 patients were included study. Using FISH, 0.15-67.0% of peripheral blood lymphocytes were found to be positive for EBER. Dual staining was used to determine EBER-positive cell phenotypes in 23 of 26 subjects (88.5%). In five of seven patients with hydroa vacciniforme-like lymphoma (an EBV-positive cutaneous T cell lymphoma), EBER-positive cells were identified as CD3(+) CD4(-) CD8(-) TCRγδ(+) T cells. Furthermore, in a 25-year-old male patient with systemic EBV-positive T cell LPD, two lymphocyte lineages were positive for EBER: CD4(+) CD8(-) and CD4(-) CD8(+) T cells. Thus, we confirmed that our newly developed assay is useful for quantifying and characterizing EBV-infected lymphocytes in EBV-associated T/NK LPD and that it can be used not only to complement the pathological diagnosis, but also to clarify the pathogenesis and to expand the spectrum of EBV-associated diseases.

Cytotoxic Chemotherapy Successfully Induces Durable Complete Remission in 2 Patients with Mosquito Allergy Resulting from Epstein-Barr Virus-Associated T-/Natural Killer Cell Lymphoproliferative Disease

Recent findings indicate that Epstein-Barr virus (EBV)-infected T-/natural killer (NK) cells play an important role in the pathogenesis of mosquito allergy, and most patients with mosquito allergy die early in life if not properly treated. Over the last 7 years, we have been using combination chemotherapy and allogeneic stem cell transplantation for the treatment of EBV-associated T-/NK cell lymphoproliferative disease (LPD) in which chronic active EBV infection and mosquito allergy were included. As of this writing, we have successfully treated 2 patients with mosquito allergy with chemotherapy in which EBV-infected T-/NK cells were eradicated. The findings suggest the possible role of chemotherapy in the treatment of EBV-associated T-/NK cell LPD.

Chronic active Epstein-Barr virus infection of natural killer cells presenting as severe skin reaction to mosquito bites

Discovered more than 40 years ago, EBV is known to exhibit tropism for lymphocytes, especially B-cells. This γ herpes virus is capable of immune evasion, producing latent infections that might lead to B-cell and other lymphoproliferative diseases. A relatively unusual target of EBV infection involves natural killer (NK) cells. Despite varying classifications, a form of chronic active EBV infection (CAEBV) involving NK cells presents with severe inflammatory and necrotic skin reactions considered pathognomonic of EBV+ NK cell lymphoproliferative disease.

Epstein-Barr virus-associated T-/natural killer cell lymphoproliferative diseases

Epstein-Barr virus (EBV) is a ubiquitous virus that infects the majority of the world population by adulthood. The major target for infection is the B lymphocyte, and acute infection causes vigorous EBV-specific killer T-cell responses exemplified clinically by acute infectious mononucleosis (IM). EBV infection usually persists latently life-long without eliciting any clinical symptoms. Rarely, active EBV infection is prolonged, with abnormal expansions of EBV-infected T or NK cells, conditions collectively defined here as EBV-associated T/NK lymphoproliferative diseases. Hemophagocytic lymphohistiocytosis (HLH), chronic active EBV infection (CAEBV), NK lymphoma/leukemia, and T-cell lymphoma are entities included in this category. Hypersensitivity to mosquito bite (HMB) represents a unique syndrome characterized by expansion of EBV-infected NK cells in the peripheral circulation and within the inflammatory skin lesions induced by mosquito bites. Target cell specificity, defects in host immune responses, and strain differences of EBV may account for ectopic EBV infections and for the unique clinical presentations characteristic of each illness. Semin Hematol 40:124-132. © 2003 Elsevier Inc. All rights reserved.

Epstein-Barr virus-associated T-/natural killer cell lymphoproliferative diseases.

Epstein-Barr virus (EBV) is a ubiquitous virus that infects the majority of the world population by adulthood. The major target for infection is the B lymphocyte, and acute infection causes vigorous EBV-specific killer T-cell responses exemplified clinically by acute infectious mononucleosis (IM). EBV infection usually persists latently life-long without eliciting any clinical symptoms. Rarely, active EBV infection is prolonged, with abnormal expansions of EBV-infected T or NK cells, conditions collectively defined here as EBV-associated T/NK lymphoproliferative diseases. Hemophagocytic lymphohistiocytosis (HLH), chronic active EBV infection (CAEBV), NK lymphoma/leukemia, and T-cell lymphoma are entities included in this category. Hypersensitivity to mosquito bite (HMB) represents a unique syndrome characterized by expansion of EBV-infected NK cells in the peripheral circulation and within the inflammatory skin lesions induced by mosquito bites. Target cell specificity, defects in host immune responses, and strain differences of EBV may account for ectopic EBV infections and for the unique clinical presentations characteristic of each illness.

Diagnosis and treatment of Epstein-Barr virus-associated natural killer cell lymphoproliferative disease.

Epstein-Barr virus (EBV) exhibits tropism for both lymphocytes and epithelial cells and can induce both replicative (productive/lytic) and latent (persistent) infections that result in a variety of human diseases. With regard to lymphocytes, latent EBV infection is linked to development of heterogeneous lymphoproliferative disease (LPD), such as B-cell LPD and T-cell/natural killer cell (T/NK cell) LPD. Unlike B-cell LPD, LPD derived from T-cells and NK cells sometimes has overlapping clinical symptoms, as well as histologic and immunophenotypic features, because both types of cells are derived from a common precursor. However, determination of cell lineage is important in classification of lymphoid neoplasms, and combined modern techniques allows us to distinguish NK cell LPD from T-cell LPD in most instances. Because NK cell LPD seems to be heterogeneous in terms of clinical features, prognosis, and diagnosis and has a monoclonal or polyclonal (or oligoclonal) nature, this review attempts to clarify recent research and clinical findings and to establish diagnostic and therapeutic strategies.

Natural killer cell lymphoproliferative disease associated with combined peripheral and autonomic neuropathy

Natural killer cell proliferation is an uncommon haematological disorder that has a number of different clinical manifestations. There have been only two prior reports linking this process with neurological disease, both reports describing peripheral neuropathy. We report the case of a young man presenting with a short history of lethargy, lower limb paraesthesia and marked weight loss who was found to have a natural killer cell lymphocytosis and features of both an autonomic and a peripheral neuropathy. The patient's clinical features responsed to a combination of cytotoxic and immunosuppressive therapy, and the patient is now clinically stable with mild ongoing lymphocytosis, diarrhoea and postural hypotension. We review the possible pathological link between natural killer cells and neurological disease.

Clonal lymphoproliferation following chronic active Epstein-Barr virus infection and hypersensitivity to mosquito bites.

In order to elucidate the possibility of lymphoproliferation in cases of chronic active Epstein-Barr virus infection (CAEBV), to clarify the clonality and genotype of proliferating lymphocytes, and to search for the factors that induce lymphoproliferation, we studied 11 cases of CAEBV, using genetical and immunological techniques. Epstein-Barr virus (EBV) DNA in peripheral mononuclear cells was detected in eight cases by Southern blotting. Among those eight cases, monoclonal proliferation of EBV DNA-positive cells was observed in three cases and oligoclonal proliferation in three cases. In the cases of monoclonal proliferation, one case manifested T-cell lymphoproliferation and the rest natural killer (NK) cell lymphoproliferation. The anti-EBV antibody titers in the study did not have any relativity to lymphoproliferation. On the other hand, three of the four cases of NK cell lymphoproliferation and one of the two cases of T-cell lymphoproliferation exhibited hypersensitivity to mosquito bites (HMB) in their clinical histories, while none of the three nonlymphoproliferation cases did. These facts indicate that T-cell and NK cell lymphoproliferative diseases (LPDs) could be more closely associated with EBV infection than we had previously expected. Also, the anti-EBV antibody titers may not be the indicator of EBV-associated LPD, and HMB may be one of the factors that induce EBV-associated LPD.

Natural killer cell lymphoproliferative disease associated with neuropathy

David Leitenberg, MD, PhD, Richard N. Eisen, MD, Jonathan M. Goldstein, MD, Yale University School of Medicine, New Haven, Connecticut, Lamber-t Busque, MD, Brigham and Womens Hospital, Boston, Massachusetts, Henry M. Rinder, MD, Peter Stys, MD, Martin E. Katz, MD, Yale University School of Medicine, New Haven, Connecticut, D. Gary Gilliland, MD, PhD, Brigham and Womens Hospital, Boston, Massachusetts, Brian R. Smith, MD, FACP, Yale University School of Medicine, New Haven, Connecticut

Aggressive Natural Killer Cell Lymphoproliferative Disease of Large Granular Lymphocytes with Leukemia-like Clinical Course in the Teminal Stage

Aggressive Natural Killer Cell Lymphoproliferative Disease of Large Granular Lymphocytes with Leukemia-like Clinical Course in the Teminal Stage