AbstractAdult T-cell Leukemia/lymphoma Research Articles

Mogamulizumab for adult T-cell leukemia/lymphoma expressing atypical phenotype CD4-/CD8+/CCR4+

Adult T-cell leukemia/lymphoma (ATL) cells are generally CD4+, CD8- and CCR4+. A 76-year-old man was diagnosed with a rare case of CD4-/CD8+ ATL in 2013. He was initially treated with the THP-COP regimen. The number of ATL cells in lymph nodes and peripheral blood (PB) and the level of soluble interleukin-2 receptor (sIL2R) were decreased initially after chemotherapy but increased within 3 months and hypercalcemia appeared. Thus, the patient was diagnosed with ATL progression. Since CCR4 expression in CD4-/CD8+ ATL cells was confirmed by flow cytometry, the patient was treated with the newly developed CCR4 antibody mogamulizumab. Treatment significantly eradicated ATL cells in PB. To our knowledge, this is the first case of CD4- ATL treated with mogamulizumab.

IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with an extremely poor prognosis. Maintaining ATLL cells in vitro is difficult and little is known about how they maintain themselves or grow in patients. Elucidating the interaction between ATLL cells and surrounding host factors might therefore provide important insights into pathophysiology. We cultured primary ATLL cells in various culture conditions using IL-2, IL-4 and feeder cells, and established two cell lines dependent on IL-2, IL-4 and a follicular dendritic cell-derived cell line, HK, in which OX40-ligand was induced. Our study indicates the importance of microenvironment in the homeostasis of ATLL.

Adult T-cell leukemia/lymphoma following elevation of serum levels of soluble cytokine receptors, sCD25 and sCD30

Adult T-cell leukemia /lymphoma (ATL) caused by human retrovirus, HTLV-1, is a neoplasm of mature T-cell. ATL is still an incurable disease with approximately 1,000 annual deaths in Japan. The useful biomarkers are required to achieve the success of treatment. In order to test whether or not two soluble cytokine receptors (sCD25 and sCD30) are useful biomarkers of the development of ATL, we investigated changes in the concentration of the two markers in 11 HTLV-1 carriers (pre/post ATL progression) and six patients with chronic ATL (pre/post acute crisis). Serum (or plasma) samples of newly diagnosed or referred ATL patients and HTLV-1 carriers were preserved in freezer to measure the level of soluble proteins, sCD25 and sCD30, using ELISA. The sCD25 concentration was measured by Cell freeN IL-2R (Kyowa Medex, Japan) and Determiner CL IL-2R (Kyowa Medex, Japan). The sCD30 concentration was measured by Human sCD30 Platinum ELISA (eBioscience). The probability of ATL development from HTLV-1 carrier state was analysed by Kaplan-Meier method. We found that the elevation of soluble cytokine receptors was one of the earlier events of ATL development. In addition, chronic type patients followed in our hospital showed sCD30 as well as sCD25 elevation prior to the diagnosis of acute crisis. Our findings suggest that a combination of sCD25 and sCD30 facilitates accurate diagnosis and intervention of ATL as useful biological markers. Further careful follow-up should be required for HTLV-1 carriers with elevated level of cytokine receptors, sCD25 and sCD30 to diagnose the early phase of ATL.

A Lack of Cellular Senescence, Formation of Microenvironment, and Role of Soluble CD30 in Development of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive leukemia/lymphoma. The long clinical latency and low incidence of ATL indicate that ATL is an age-related disease with genetic changes that are involved in malignant transformation and monoclonal expansion of human T lymphotropic virus type 1 (HTLV-1) infected cells. The question remains as to how the ATL cells acquire monoclonal proliferation rather than undergo senescence. It was implied that aberrant cellular proteins such as p53, JAK-STAT and Bcl-xL were associated with the development of ATL. HTLV-1-infected cells and ATL cells (partial) express CD30. Soluble CD30 (sCD30) may impair the interaction of CD30 ligand+ cells with CD30+ ATL cells. Probably HTLV-1-infected T-cells migrate to the lung due to agerelated changes of pulmonary immune system. Thereafter monoclonal proliferation of infected cells following antigen presentation forms a local network between cytokines and cytokine receptors. During the remodeling of the pulmonary tissue, CD30+ ATL cells and matrix metalloproteinases can play an important role in forming tumor microenvironment. Furthermore, soluble cytokine receptors may support the clonal proliferation and invasion of ATL cells and tumor microenvironment is created in extra nodal lesions such as lung. Accordingly, sCD30 level could be applied to detection of microenvironment formation for tumor stem cells and their monitoring in ATL.

Augmentation of donor-derived Tax-specific CTL responses by a novel Tax epitope-specific CD4+ helper T-cells in ATL patients after allogeneic hematopoietic stem cell transplantation

Adult T-cell leukemia/ lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) and characterized by extremely poor prognosis because of intrinsic drug resistance to cytotoxic agents. Recently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been shown to be an effective treatment for ATL due to graft-versus-leukemia effects. However, donor-derived HTLV-1-specific T-cell responses in ATL patients after allo-HSCT are not well understood. In this study, blood samples from 15 ATL patients at 180 days following allo-HSCT from seronegative donors were screened for IFN-g production of donor-derived T-cells against Tax protein. Among 15 patients, Tax-specific T-cell responses were observed in 11 patients. Direct detection with Tax/MHC class I tetramers revealed that donor-derived Tax-specific CD8+ cytotoxic T-lymphocytes (CTLs) were present in 12 of 15 patients. We then identified a novel Tax epitope (Tax155-167) presented by HLA-DR1 (HLA-DRB1*0101) and examined the presence of Tax-specific CD4+ T-cells in 3 HLA-DR1+ patients after allo-HSCT using a newly generated Tax155-167/HLA-DR1 tetramer. Tax155-167-specific CD4+ T-cells were found to be present in all HLA-DR1+ patients tested. Furthermore, in vitro stimulation of PBMCs from HLA-DR1+ HLA-A*2402+ patients with both Tax155-167 and HLA-A*2402-restricted CTL epitope (Tax301-309) led to robust expansion of Tax301-309-specific CTLs. Our results suggest that donor-derived HTLV-1-specific both CD4+ and CD8+ T-cells could be induced in ATL patients after allo-HSCT from seronegative donors, probably due to exposure to HTLV-1 antigens from recipient-derived ATL cells, and the HTLV-1-specific CD4+ T-cells may contribute to efficient induction of donor-derived HTLV-1-specific CTL responses.

NDRG2 plays a pivotal role in ATLL leukaemogenesis by regulating the PTEN-mediated PI3K/AKT signalling pathway

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive T-cell leukemia/lymphoma that is etiologically linked to infection by human T-cell lymphotropic virus type 1 (HTLV-1). To find candidate causative genes for ATLL development, we used an integrative genomic analysis of ATLL and identified N-myc downstreamregulated gene 2 (NDRG2) as a candidate tumour suppressor gene on chromosome 14q11. Here we demonstrate that NDRG2 is a novel PTEN-interacting protein and recruits protein phosphatase 2A to facilitate the dephosphorylation of PTEN at the Ser380, Thr382, and Thr383 (STT) cluster within the C terminus. Although the PI3K/ AKT signalling pathway is frequently activated in ATLL cells, neither the genetic alterations of the PTEN and PIK3CA genes nor the transcriptional down-regulation of PTEN expression were detected in ATLL. We found that activation of the PI3K/AKT signalling pathway in ATLL is mediated through hyperphosphorylation of PTEN-STT, a well-known mechanism of PTEN inactivation, by down-regulation of NDRG2 expression. Moreover, we found that NDRG2 deficiency in mice results in constitutive PI3K/AKT activation in various organs and high incidence of T-cell lymphoma and other types of cancer. Since down-regulation of NDRG2 expression via promoter methylation has been reported in various types of cancer, activation of the PI3K/AKT pathway by the enhanced PTEN-STT phosphorylation through the inactivation of NDRG2 is crucial for the development of a wide range of cancer cells including ATLL, which harbor no activating genetic alterations in the PI3K/AKT pathway.

Mogamulizumab, an anti-CCR4 monoclonal antibody, is a potent therapeutic option for adult T-cell leukemia-lymphoma

Adult T-cell leukemia-lymphoma (ATL) is a rare and aggressive T-cell malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1). ATL remains an extremely difficult disease to treat, and therefore, the development of novel therapies is highly needed. Because CC chemokine receptor 4 (CCR4) is frequently overexpressed on ATL cells from patients (Clin Cancer Res. 2003;9:3625), mogamulizumab, a defucosylated humanized anti-CCR4 antibody, has been developed for the treatment of ATL in Japan. In a phase I study in patients with relapsed CCR4-positive T-cell malignancies, mogamulizumab was well tolerated up to 1 mg/kg and encouraging efficacy was observed (JCO 2010;28:1591). In a subsequent pivotal phase II study in CCR4-positive relapsed ATL patients, mogamulizumab exhibited an overall response rate (ORR) of 50% including 8 complete responses (CR) (JCO 2012;30:837), leading to its approval in Japan in 2012 for relapsed/refractory ATL. Furthermore, with the aim of establishing a new standard therapy for untreated ATL, we conducted a randomized phase II study of VCAP-AMP-VECP, a dose-intensified multi-agent chemotherapy, with or without mogamulizumab (arm-A or arm-B). The CR rate (primary endpoint) and ORR (secondary endpoint) were higher in arm-A than in arm-B (52% vs. 33% and 86% vs. 75%, respectively). Median progression-free survival was also longer in arm-A (259 days vs. 192 days). The most common treatment-related AEs were hematological toxicity in both arms. These results suggest that mogamulizumab could provide a new effective treatment option for both relapsed/refractory and untreated ATL. Trial registration http://ClinicalTrials.gov NCT01173887

Clinical Value of Serum Soluble CD30 Levels in Adult T-Cell Leukemia/ Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is an incurable neoplasm of mature T-cells with a median survival time of approximately one year. The aim of this study was to compare the clinical value of soluble CD30 (sCD30) levels with soluble IL-2 receptor α chain (sIL-2R) levels in two different clinical settings of ATLL patients; before an initial therapy of chemotherapy or gastric resection (n=32), and before allogeneic hematopoietic stem cell transplantation (HSCT; n=24). All patients completed the 2-year follow-up. Both sIL-2R (p=0.016) and sCD30 (p=0.030) levels were significant predictors of overall survival before the initial therapy. The number of ATLL cells in peripheral blood (PB) was correlated with sCD30 levels (Spearman’s correlation coefficient, ρ=0.46; p=0.009) but not with sIL-2R levels (ρ=0.16; P=0.38). Patients who survived for longer than two years, and for whom the percentage of ATLL cells in PB were <5%, displayed relatively low sCD30 levels, but this tendency for low sCD30 levels was not observed in longterm survivors whose ATLL cells constituted ≥5% of PB cells. sIL-2R (p=0.041) and sCD30 (p=0.0003) values were both significant predictors of overall survival in HSCT, but sCD30 levels predicted more patients with early death than were predicted by sIL-2R levels. Combination of sCD30 and CRP levels showed high sensitivity and specificity for detection of early death (within 100 days) following HSCT (81.8% and 84.6%, respectively). These results suggest that analysis of sCD30 levels may be useful for prediction of overall survival in ATLL patients, especially before HSCT. These findings would alter the treatment strategy and improve the prognosis of ATLL.

Biomarkers and clonality before and after treatment

Adult T-cell leukemia-lymphoma (ATLL) is a disease with dismal prognosis urging new therapies. Few biomarkers have been identified to predict disease outcome in ATLL, however, routine testing for these is not widely available. The first line treatment option for ATLL can vary according to disease subtype, investigator’s choice, or institutional practices. For instance, experience at some centers suggest that there are patients with ATLL who can benefit from zidovudine (AZT)/interferon alpha (IFNα) therapy without requiring chemotherapy upfront. It has been reported that p53 gene alterations or MUM-/IRF-4 expression status may influence response to AZT/IFNα. More recently, the use of the anti-CD30 monoclonal antibody brentuximab vedotin is being advocated for the treatment of CD30+ T-cell malignancies, including ATLL. Therefore, establishing biomarkers that can help guide therapeutic decisions for ATLL would be ideal. Updated results and the usefulness of testing for some of these biomarkers will be discussed.

Tax inflicts DNA damage through activation of Nitric Oxide production

Adult T-cell Leukemia-Lymphoma (ATLL) is an aggressive and fatal malignancy of CD4+ T-lymphocytes associated with HTLV-1 infection, and an effective treatment is not yet available. The molecular mechanism underlying ATLL has not been fully elucidated. However, accumulation of genomic instability is believed to be a driving force for leukemogensis. How genomic instability accumulates in HTLV-1 infected cells is currently under intensive investigation. Recently, we found that the HTLV-1 viral oncoprotein, Tax, which is implicated in the chronic inflammatory response, induces DNA Double Strand Breaks (DDSB). Tax is known to activate the key T-cell inflammatory transcription factors, NF-kB, and this activation is critical for the leukemogenic process associated with HTLV-1 infection. Of note, we found that inducible nitric oxide synthase (iNOS), the enzyme that catalyzes the production of nitric oxide (NO) is highly expressed in HTLV-1 and Tax expressing cells. Interestingly, we show that the expression of iNOS is Tax-dependent and specifically requires the classical NF-kB pathway. In addition, IRF-1, the interferon regulatory factor that collaborates with NF-kB transcription factors to activate iNOS expression was also found activated by the JAK/STAT pathway. Our results show a correlation between the number of DDSB and the production of NO in tumors isolated from Tax transgenic mice. We also observed a dramatic reduction of DDSB when NO production was inhibited. Determination of the impact of NO on tumors in an ATLL mouse model will open a new area in the development of alternative strategies for the treatment/prevention of ATLL.

Soluble CD30 is a new biomarker to predict two-year overall survival of adult T cell leukemia/lymphoma patients

Adult T-cell leukemia/lymphoma (ATLL) caused by human retrovirus, HTLV-1, is a neoplasm of mature T-cell. In Japan, more than a thousand patients with ATLL die every year incurable with median survival time less than one year. We aim to investigate clinical value of soluble CD30 (sCD30) levels in sera on prediction of short term mortality and overall survival (OS) in ATLL patients.

The kinetics of HTLV-1 proviral load after allogeneic hematopoietic cell transplantation with reduced intensity conditioning regimen; a comparison with that from sibling donors and that from unrelated donors

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy that is caused by human T-lymphotropic virus type 1 (HTLV-1) with poor prognosis. We have reported the feasibility and efficacy of allogeneic hematopoietic cell transplantation with reduced intensity conditioning (RIC-HCT) for elderly patients with ATL, and have also shown that in more than half of patients the HTLV-1 proviral load (HTLV-PL) decreased to an undetectable level after RIC-SCT, suggested presence of anti HTLV-1 effects. In this study, we try to compare the kinetics of HTLV-PL after RIC-SCT from HTLV-1 antibody negative sibling donor (SD) with that from unrelated donors (UD), all of whom were HTLV-1 antibody negative. Fourteen patients were included in the SD group, and fifteen patients were in UD group. The HTLV-PL decreased to an undetectable revel in 11 of 14 patients (78.6%) in the SD group and 13 of 15 (86.7%) in the UD group with in 120 days after RIC-SCT. In short term, the kinetics of the HTLV-PL after RIC-SCT from UD was almost similar to that from HTLV-1 negative SD. Looking at the long term follow-up results, the HTLV-PL remains to be an undetectable level in only 2 of 11 (18.2%) patients in the SD group (median follow up 111 months [101-122])), on the other hand, 7 of 13 (53.8%) patient in the UD group (24 month [20-36]). RIC-HCT from UD tends to have better anti-HTLV-1 effect, compared with that from SD, but not conclusive because of the short follow-up period.

Clinical features and outcome of adult T-cell leukemia/lymphoma: University of Miami experience

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis caused by HTLV-I. Miami is proximal to the Caribbean, where HTLV-I is endemic. We have identified at least 140 cases between 1987 and 2013. A total of 108 patients have been analyzed for treatment response, including 51 acute, 50 lymphomatous, 5 chronic (4 unfavorable), and 2 smoldering types. The median overall survival for acute and lymphomatous was 6 and 10 months respectively, and not reached for chronic and smouldering types. Fifty-one patients (33 acute, 11 lymphomatous, 5 chronic, and 2 smouldering) were treated with high-dose AZT/interferon (IFN) as first line therapy. The complete and overall response rates (CR and ORR) for acute/unfavorable chronic vs. lymphomatous types were 27% vs. 9%, and 57% vs. 9% respectively. Three out of 4 (75%) unfavorable chronic type patients responded to AZT/IFN (2 CR, and 1 partial response). Seventy-three patients received chemotherapy at some point during their treatment. The CR rate and ORR for acute/unfavorable chronic vs. lymphomatous-type patients treated with chemotherapy-based regimens were 33 % vs. 17%, and 60% vs. 73% respectively. Five acute type patients who had failed AZT/IFN achieved remission after chemotherapy. By contrast, patients treated with AZT/IFN as second line therapy generally did not respond. Finally, we observed several long-sustained responses in acute and unfavorable chronic subtypes treated with first line AZT/ IFN alone translating into a survival benefit. A comprehensive stratified analysis of clinical characteristics, pertinent immunophenotypic markers, and treatment outcome will be presented at the meeting.

Abstract LB-127: HTLV-1 Tax inflicts severe DNA damage through the activation of nitric oxide production: A credible pathway for transformation of HTLV-1 infected cells.

Abstract Adult T-cell Leukemia-Lymphoma (ATLL) is an aggressive and fatal malignancy of CD4+ T-lymphocytes associated with HTLV-1 infection, and an effective treatment is not yet available. The exact molecular mechanism underlying ATLL has not been fully elucidated. Although the activation of cell proliferation and inhibition of tumor suppressors are considered key contributors to the leukemogenesis process, the accumulation of DNA damage and genomic instability are believed to be the driving force for tumorigenesis and are known to be a hallmark of cancer cells. How genomic instability accumulates in cancer remains an elusive question. One of the most serious forms of genomic instability is DNA Double Strand Breaks (DDSB) because they pose problems for transcription, replication and chromosome segregation. We have recently shown that the HTLV-1 oncoprotein Tax induces DDSB. In addition, Tax has been found to constitutively activate the key T-cell inflammatory pathway, NF-kB, and this activation is critical for the leukemogenic process associated with HTLV-1 infection. In the present study, we investigated whether any of the NF-kB target genes is critical in inducing DDSB. Of note, we found that the inducible nitric oxide synthase (iNOS), the enzyme that catalyzes the production of nitric oxide (NO) in T-cells, is a target of the NF-kB pathway and is highly expressed in HTLV-1 and Tax expressing cells. Nitric oxide is an important cellular signaling molecule involved in many physiological and pathological processes and is a part of the network of reactive species that inflict DNA damage as a defense mechanism after infection. Interestingly, our results show a correlation between the number of DDSB and the production of NO in tumors isolated from Tax transgenic mice. We also observed a dramatic reduction of DDSB when NO production was inhibited, indicating that Tax induces DNA damage through the activation of NO. Determination of the impact of NO on tumors in an ATLL mouse model will open a new area in the development of alternative strategies for the treatment/prevention of ATLL, and the conclusions will be directly relevant to a better understanding of many types of cancer. Citation Format: Hicham Baydoun, Lee Ratner. HTLV-1 Tax inflicts severe DNA damage through the activation of nitric oxide production: A credible pathway for transformation of HTLV-1 infected cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-127. doi:10.1158/1538-7445.AM2013-LB-127

Adult T-Cell Leukemia-Lymphoma during Pregnancy

Adult T-cell leukemia-lymphoma (ATL) is an uncommon highly aggressive T-cell lymphoma associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. It is rarely encountered during pregnancy and is particularly challenging to treat due to its aggressive nature and because of the lack of robust data on optimal chemotherapy. We report a case of a Jamaican immigrant diagnosed with ATL during pregnancy.

Quantitative differences in antibody responses between normal donors HAM/TSP patients, asymptomatic carriers, and ATL patients from Jamaica: can they be used to estimate risk of disease?

Adult T cell leukemia/lymphoma (ATL) and HTLV-1associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-I infection. In these patients, the antibody titer and provirus load are elevated compared to levels in asymptomatic carriers (AC). These methods that determine HTLV-I infection do not differentiate between AC, HAM/TSP patients, and ATL patients. We have reported on a Luciferase Immunoprecipitation System (LIPS), a highly sensitive, quantitative technology that can efficiently detect HTLV-I antibody responses in serum of infected individuals [1]. We extended our preliminary analysis to detect anti-HTLV-I antibodies in samples from 439 persons from Jamaica: normal donors (ND), AC, ATL, and HAM/TSP patients. The antibody responses of ND differed significantly from those of HTLV-I infected patients for all three immunodominant proteins. More specifically, HAM/ TSP patients were 2 times more likely to have an antibody response >1 standard deviation above the mean for ACs in gag (Odds Ratio (OR) = 2.45, 95% confidence interval [CI] = 1.23-4.88) and were 5 times more likely to exceed that threshold in env (OR = 5.27, CI = 2.5111.08). ATL patients were 1.8 times more likely to exceed that threshold in env (OR = 1.82, CI = 1.01-3.27) and 70% less likely to exceed that threshold in tax (OR = 0.30, CI = 0.11-0.51). HAM/TSP patients had significantly higher antibody responses in gag, env, and tax compared to ATL patients. These significant differences between antibody responses in HTLV-I infected individuals may be a useful diagnostic tool in the future.

Overexpression of SIRT1 and induction of apoptosis by its inhibition in adult T-cell leukemia cells

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide (NAD +)-dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, due to its ability to deacetylate numerous substrates, such as histone and NFB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family, and degradation of SIRT1 in the nucleus. Interestingly, NAD+ augmented sirtinolinduced apoptosis in leukemic cell lines. Thus, the SIRT1 inhibitor acted as a tumor suppressor, where NAD+ accelerated the SIRT1 inhibitor-induced apoptosis. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells, and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.

Can we cure HTLV-I associated Adult T cell Leukemia Lymphoma?

Adult T cell leukemia (ATL) is one of the rare human cancers initiated by a transforming retrovirus, HTLV-I. After many years of controversy, it is now accepted that the viral transactivator protein Tax plays a critical role in initiating the leukemic process, because Tax transgenics develop a disease with striking ATL features. However, its role in the maintenance of the lymphoproliferation remains still a matter of debate. Long-term prognosis of ATL patients remains extremely poor. In acute ATL, well conducted Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis but long-term survival is poor when these patients are managed with a watchful-waiting policy or with chemotherapy. We recently realized a worldwide meta-analysis showing that the combination of zidovudine and interferon-alpha (IFN) is highly effective in the leukemic subtypes of ATL and should be considered as standard first line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as patients with acute ATL and wild type p53. ATL lymphoma patients may benefit from initial induction therapy based on aggressive chemotherapy regimen in addition to or followed by antiretroviral therapy with AZT/IFN. In all patients, in order to prevent the occurrence of resistance and relapse, clinical trials assessing bone marrow transplantation additional targeted therapies such as arsenic/IFN combination or monoclonal antibodies, are mandatory after achieving CR. In that sense, we recently reported that the combination of arsenic trioxide, IFN, known to trigger Tax proteolysis in addition to zidovudine, yielded unprecedented response rates in chronic ATL patients, and may prevent relapses in ATL lymphoma responding patients after chemotherapy. To investigate the molecular mechanism of therapeutic action in vivo, we used Tax transgenic mice that develop a disease with striking ATL features. We demonstrate that the combination of arsenic trioxide and IFN cures Tax-driven murine ATLs through selective targeting of leukemia initiating cell (LIC) activity. Importantly, this effect requires proteasome function. Overall, our findings strongly suggest that in this model ATL LICs are addicted to the iral Tax oncoprotein and open the prospect of new strategies to cure ATL.

TP53 and p16INK4A mutations in adult-T cell leukemia/lymphoma (ATL) in Bahia (Brazil)

ATL is an aggressive malignancy associated with the HTLV-1. The development of ATL is believed to involve a multitude of factors that include the accumulation of genetic alterations. The aim of this study was to analyze the presence of mutations in the TP53, p16INK4A, p15INK4B, K-ras, PI3K and EGFR genes in ATL patients from Bahia (Brazil) with the acute and chronic subtypes. Fourteen patients with acute ATL and five with chronic ATL were included. Exons 4-9 of the TP53 gene, exons 1-3 of the p16INK4A gene, exons 1-2 of the p15INK4B gene, exons 18-21 of the EGFR gene and exons 9 and 21 of the PI3Ka gene were investigated using PCR followed by sequencing. Mutations at codons 12 and 13 of the K-ras gene were analyzed by RFLP following PCR amplification. In 5 of the 19 ATL patients (26%), missense mutations were observed in the TP53 gene. All of these patients had the acute subtype. Alterations were detected in exon 5 (codons 155 and 181), exon 7 (codon 248) and exon 8 (codon 282). Mutations in codons 155, 181 and 282 had not previously been described in ATL. Missense mutation was observed in p16INK4A in only one patient with acute ATL who did not have alterations in the TP53 gene. Point mutations in p15INK4B, K-ras, EGFR and PI3Ka genes were not found. These results are in agreement with the findings of previous studies suggesting that mutations of the TP53 and p16INK4A genes may play a role in aggressive ATL.

Adult T-cell leukemia–lymphoma: current treatment strategies and novel immunological approaches

Adult T-cell leukemia–lymphoma (ATL) is a peripheral T-cell malignancy, closely associated with human T-cell lymphotropic virus type I infection. Clinically, ATL is classified into four subtypes: acute, lymphoma, chronic and smoldering type. Although the prognosis of chronic and smoldering-type ATL is relatively good, that of patients with acute- or lymphoma-type ATL still remains extremely poor. Zidovudine/IFN-α therapy seems to be promising, although its efficacy has not yet been confirmed in well-designed prospective studies. High-dose chemotherapy with the support of autologous transplantation does not improve outcome. Allogeneic stem cell transplantation is promising and approximately 40% of aggressive ATL patients are expected to survive long-term, although transplantation-related mortality is as high as 40–50%. Stem cell transplantation using reduced-intensity conditioning is also effective and safer, with graft-versus-ATL and graft-versus-human T-cell lymphotropic virus type I effects observed after transplantation. Novel approaches including new agents such as purine nucleoside phosphorylase inhibitors and histone deacetylase inhibitors, or targeted immunotherapy using antichemokine receptor-4 antibody or dendritic cell/peptide vaccine are also warranted.