A preclinical model for the ATLL lymphoma subtype with insights into the role of microenvironment in HTLV-1-mediated lymphomagenesis

Abstract \uef7f View references (83) Adult T cell Leukemia/Lymphoma (ATLL) is a mature T cell malignancy associated with Human T cell Leukemia Virus type 1 (HTLV-1) infection. Among its four main clinical subtypes, the prognosis of acute and lymphoma variants remains poor. The long latency (3-6 decades) and low incidence (3-5%) of ATLL imply the involvement of viral and host factors in full-blown malignancy. Despite multiple preclinical and clinical studies, the contribution of the stromal microenvironment in ATLL development is not yet completely unraveled. The aims of this study were to investigate the role of the host microenvironment, and specifically fibroblasts, in ATLL pathogenesis and to propose a murine model for the lymphoma subtype. Here we present evidence that the oncogenic capacity of HTLV-1-immortalized C91/PL cells is enhanced when they are xenotransplanted together with human foreskin fibroblasts (HFF) in immunocompromised BALB/c Rag2-/-\u3b3c -/-mice. Moreover, cell lines derived from a developed lymphoma and their subsequent in vivo passages acquired the stable property to induce aggressive T cell lymphomas. In particular, one of these cell lines, C91/III cells, consistently induced aggressive lymphomas also in NOD/SCID/IL2R\u3b3c KO (NSG) mice. To dissect the mechanisms linked to this enhanced tumorigenic ability, we quantified 45 soluble factors released by these cell lines and found that 21 of them, mainly pro-inflammatory cytokines and chemokines, were significantly increased in C91/III cells compared to the parental C91/PL cells. Moreover, many of the increased factors were also released by human fibroblasts and belonged to the known secretory pattern of ATLL cells. C91/PL cells co-cultured with HFF showed features reminiscent of those observed in C91/III cells, including a similar secretory pattern and a more aggressive behavior in vivo. On the whole, our data provide evidence that fibroblasts, one of the major stromal components, might enhance tumorigenesis of HTLV-1-infected and immortalized T cells, thus throwing light on the role of microenvironment contribution in ATLL pathogenesis. We also propose that the lymphoma induced in NSG mice by injection with C91/III cells represents a new murine preclinical ATLL model that could be adopted to test novel therapeutic interventions for the aggressive lymphoma subtype

Chronic adult T-cell Leukemia in a young male after blood transfusion as a newborn

Human T-cell Lymphotropic virus type 1 (HTLV-1) is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HTM/TSP). Areas of extremely high HTLV-1 prevalence are surrounded by areas of middle or very low prevalence. ATLL is an aggressive lymphoproliferative malignancy of peripheral T cells, with an incidence of less than 5% in HTLV-1-infected individuals. ATLL develops in the majority of cases in individuals who were infected with HTLV-1 by their mothers due to prolonged breastfeeding. In non-endemic areas, ATLL is usually limited to immigrants from endemic regions. Very few cases of ATLL have been diagnosed in recipient patients few years after an organ transplantation or blood transfusion worldwide. Achieving an accurate and fast diagnosis of ATLL can be challenging due to the lack of professional experience, delayed consultation and difficulty in its subclassification. We present a case of a delayed onset of a chronic ATLL in an 18-years-old male that was transfused with blood components as a premature newborn in Buenos Aires, a non-endemic city of South America.Fil: Colucci, Magalí. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cánepa, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ruggieri, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Berini, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Halperin, Nora Silvia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rojas, Francisca. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Altube, Alejandra. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cabral Lorenzo, María Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Deves, Alberto. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Hermine, Olivier. Universite de Paris V; FranciaFil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Diagnostic Utility of SOX4 Expression in Adult T-Cell Leukemia/Lymphoma

Differentiation between adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is often challenging based on pathological findings alone. Although serum anti-HTLV-1 antibody positivity is required for ATLL diagnosis, this information is often not available at the time of pathological diagnosis. Therefore, we examined whether the expression of SOX4 and p16 would be helpful for differentiating the two disease entities. We immunohistochemically examined SOX4 and p16 expression (which have been implicated in ATLL carcinogenesis) in 11 ATLL patients and 20 PTCL-NOS patients and classified them into four stages according to the percentage of positive cells. Among the ATLL cases, 8/11 (73%) were SOX4-positive, while only 2/20 (10%) PTCL-NOS cases expressed SOX4. The mean total score was 4.2 (standard deviation (SD): 0.61) in the ATLL group and 0.50 (SD: 0.46) in the PTCL-NOS group (p < 0.001). Positive expression of p16 was noted in 4/11 (36%) patients with ATLL and 3/20 (15%) patients with PTCL-NOS, with mean total scores of 1.9 (SD: 0.64) and 0.70 (SD: 0.48) in the ATLL and PTCL-NOS groups, respectively (p = 0.141). These results suggest that SOX4 may be strongly expressed in ATLL compared to PTCL-NOS cases. Therefore, it may be helpful to perform immunohistochemical staining of SOX4 when pathologists face challenges discriminating between ATLL and PTCL-NOS

Cytogenetic analysis of adult T-Cell leukemia/ lymphoma: evaluation of a Caribbean cohort

Adult T-cell leukemia/lymphoma (ATLL) is a rare and highly aggressive type of peripheral T-cell lymphoma associated with human T-lymphotropic virus, type I (HTLV-I) infection. ATLL has a long latency and only a small percentage of HTLV-I infected individuals develop ATLL, suggesting the requirement of additional genetic events for neoplastic transformation of HTLV-I infected lymphocytes. The disease is endemic in several regions of the world, in particular, southwestern Japan and the Caribbean basin. The clinical features of Caribbean ATLL have been reported to differ from Japanese cases, includ- ing a younger age at diagnosis, higher frequency of the lymphomatous subtype, and a more aggressive clinical course [1–7]. A number of publications have described the cytogenetic profile of Japanese ATLL [8–11]; however, cytogenetic data on Caribbean ATLL are limited [5,6]. In this study, we assessed the cytogenetic alterations in a large series of Caribbean ATLL cases to investigate whether the differences in the types and frequencies of karyotype abnormalities account for the reported differ- ences in clinical presentation and outcome between Japanese and Caribbean patients

LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway

Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD

Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha

Adult T-cell leukemia-lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon alpha (IFNalpha). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT-IFNalpha therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT-IFNalpha differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT-IFNalpha therapy may provide novel insights into the mechanisms of action in ATLL

An improved tool of water data analytics for flowmeters data

This paper presents an improved tool for data validation and reconstruction of flowmeters. These sensors are installed in the Catalonia regional water network from Barcelona (Spain). Here a new time series model with exogenous variable is proposed with excellent results for data validation. It is postulated that the integration of the electronics alarms, along with other tests about the daily data accumulated and a later analysis of the data reconstruction allow to improve the results of the existing tools. This is accomplished by decreasing the false alarms and missing alarms of more than 6000 hourly data retrieved from more than 200 flowmeters each day. This new tool provides reliable information daily reliable information of the state of the water network. This information could potentially contribute to optimally control and manage this large and complex water network.Postprint (published version

Knowledge extraction from raw data in water networks: application to the Barcelona supramunicipal water transport network

Critical Infrastructure Systems (CIS) such as the case of potable water transport network are complex large-scale systems, geographically distributed and decentralized with a hierarchical structure, requiring highly sophisticated supervisory and real-time control (RTC) schemes to ensure high performance achievement and maintenance when conditions are non-favorable due to e.g. sensor malfunctions (drifts, offsets, problems of batteries, communications problems,...). Once the data are reliable, a process to transform these validated data into useful information and knowledge is key for the operating plan in real time (RTC). And moreover, but no less important, it allows extracting useful knowledge about the assets and instrumentation (sectors of pipes and reservoirs, flowmeters, level sensors, ...) of the network for short, medium and large term management plans. In this work, an overall analysis of the results of the application of a methodology for sensor data validation/reconstruction to the ATLL water network in the city of Barcelona and the surrounding metropolitan area since 2008 until 2013 is described. This methodology is very important for assessing the economic and hydraulic efficiency of the network.Peer ReviewedPostprint (published version

MicroRNA expression in HTLV-1 infection and pathogenesis

Our laboratory is examining the profiles of microRNA expression in ATLL cells and infected T-cell lines using microarrays and small RNA libraries. Microarray analysis of ATLL samples revealed 6 upregulated and 21 downregulated microRNAs in ATLL cells compared to CD4+ T-cell controls. Potential targets for deregulated microRNAs were identified by integrating microRNA and mRNA expression profiles. Current experiments are aimed at verifying these predicted microRNA-target interactions

High prevalence of bronchiectasis is linked to HTLV-1-associated inflammatory disease.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus, is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia/lymphoma (ATLL). The reported association with pulmonary disease such as bronchiectasis is less certain. METHODS: A retrospective case review of a HTLV-1 seropositive cohort attending a national referral centre. The cohort was categorised into HTLV-1 symptomatic patients (SPs) (ATLL, HAM/TSP, Strongyloidiasis and HTLV associated inflammatory disease (HAID)) and HTLV-1 asymptomatic carriers (ACs). The cohort was reviewed for diagnosis of bronchiectasis. RESULT: 34/246 ACs and 30/167 SPs had been investigated for respiratory symptoms by computer tomography (CT) with productive cough +/- recurrent chest infections the predominant indications. Bronchiectasis was diagnosed in one AC (1/246) and 13 SPs (2 HAID, 1 ATLL, 10 HAM/TSP) (13/167, RR 19.2 95 % CI 2.5-14.5, p = 0.004) with high resolution CT. In the multivariate analysis ethnicity (p = 0.02) and disease state (p < 0.001) were independent predictors for bronchiectasis. The relative risk of bronchiectasis in SPs was 19.2 (95 % CI 2.5-14.5, p = 0.004) and in HAM/TSP patients compared with all other categories 8.4 (95 % CI 2.7-26.1, p = 0.0002). Subjects not of African/Afro-Caribbean ethnicity had an increased prevalence of bronchiectasis (RR 3.45 95 % 1.2-9.7, p = 0.02). CONCLUSIONS: Bronchiectasis was common in the cohort (3.4 %). Risk factors were a prior diagnosis of HAM/TSP and ethnicity but not HTLV-1 viral load, age and gender. The spectrum of HTLV-associated disease should now include bronchiectasis and HTLV serology should be considered in patients with unexplained bronchiectasis