Adult T cell Leukemia-Lymphoma

Adult T-cell leukemialymphoma (ATL) was first described in 1977 as a distinct clinico-pathological entity with a suspected viral etiology. Subsequently, a novel RNA retrovirus, human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) was isolated from a cell line established from the leukemic cells of an ATL patient, and the finding of a clear association with ATL led to its inclusion among human carcinogenic pathogens. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. HTLV-1 infection early in life, presumably from breast feeding, is crucial in the development of ATL. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types defined by organ involvement, and LDH and calcium values. In cases of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL), intensive chemotherapy such as VCAP-AMP-VECP is usually recommended. In cases of favorable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended although the long term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation is also promising for the treatment of aggressive ATL possibly reflecting graft vs. ATL effect. Several new agent-trials for ATL are ongoing and in preparation, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody. Two steps should be considered for the prevention of HTLV-1-associated ATL. The first is the prevention of HTLV-1 infections and the second is the prevention of ATL among HTLV-1 carriers. So far, no agent has been found to be effective for the latter. Further investigation on the pathogenesis of ATL is crucial for the prevention and treatment of this refractory leukemialymphoma

Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells

<p>Abstract</p> <p>Background</p> <p>HTLV-1 causes adult T-cell leukemia (ATL). Although there have been many studies on the oncogenesis of the viral protein Tax, the precise oncogenic mechanism remains to be elucidated. Recently, a new viral factor, HTLV-1 basic Zip factor (HBZ), encoded from the minus strand mRNA was discovered and the current models of Tax-centered ATL cell pathogenesis are in conflict with this discovery. HBZs consisting of non-spliced and spliced isoforms (HBZ-SI) are thought to be implicated in viral replication and T-cell proliferation but there is little evidence on the HBZ expression profile on a large scale.</p> <p>Results</p> <p>To investigate the role of HBZ-SI in HTLV-1 provirus-positive cells, the HBZ-SI and Tax mRNA loads in samples with a mixture of infected and non-infected cells were measured and then adjusted by dividing by the HTLV-I proviral load. We show here that the HBZ-SI mRNA level is 4-fold higher than non-spliced HBZ and is expressed by almost all cells harboring HTLV-1 provirus with variable intensity. The proviral-adjusted HBZ-SI and Tax quantification revealed a characteristic imbalanced expression feature of high HBZ and low Tax expression levels in primary ATL cells or high HBZ and very high Tax levels in HTLV-1-related cell lines (cell lines) compared with a standard expression profile of low HBZ and low Tax in infected cells. Interestingly, according to the mutual Tax and HBZ expression status, HTLV-1-related cell lines were subcategorized into two groups, an ATL cell type with high HBZ and low Tax levels and another type with high Tax and either high or low HBZ, which was closely related to its cell origin.</p> <p>Conclusion</p> <p>This is the first comprehensive study to evaluate the mutual expression profile of HBZ and Tax in provirus-positive cells, revealing that there are quantitative and relative characteristic features among infected cells, primary ATL cells, and cell lines.</p

High Human T Cell Leukemia Virus Type-1(HTLV-1) Provirus Load in Patients with HTLV-1 Carriers Complicated with HTLV-1-unrelated disorders

<p>Abstract</p> <p>Background</p> <p>To address the clinical and virological significance of a high HTLV-1 proviral load (VL) in practical blood samples from asymptomatic and symptomatic carriers, we simultaneously examined VL and clonal expansion status using polymerase chain reaction (PCR) quantification (infected cell % of peripheral mononuclear cells) and Southern blotting hybridization (SBH) methods.</p> <p>Results</p> <p>The present study disclosed extremely high VL with highly dense smears with or without oligoclonal bands in SBH. A high VL of 10% or more was observed in 16 (43.2%) of a total of 33 samples (one of 13 asymptomatic carriers, 8 of 12 symptomatic carriers, and 7 of 8 patients with lymphoma-type ATL without circulating ATL cells). In particular, an extremely high VL of 50% or more was limited to symptomatic carriers whose band findings always contained at least dense smears derived from polyclonally expanded cells infected with HTLV-1. Sequential samples revealed that the VL value was synchronized with the presence or absence of dense smears, and declined at the same time as disappearing dense smears. Dense smears transiently emerged at the active stage of the underlying disease. After disappearance of the smears, several clonal bands became visible and were persistently retained, explaining the process by which the clonality of HTLV-1-infected cells is established. The cases with only oligoclonal bands tended to maintain a stable VL of around 20% for a long time. Two of such cases developed ATL 4 and 3.5 years later, suggesting that a high VL with oligoclonal bands may be a predisposing risk to ATL.</p> <p>Conclusion</p> <p>The main contributor to extremely high VL seems to be transient emergence of dense smears detected by the sensitivity level of SBH, corresponding to polyclonal expansion of HTLV-1-infected cells including abundant small clones. Major clones retained after disappearance of dense smears stably persist and acquire various malignant characteristics step by step.</p

Treatment outcome of elderly patients with aggressive adult T cell leukemia-lymphoma: Nagasaki University Hospital experience

VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1 %, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6 %, respectively. Eleven of 34 patients (32 %) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7 %, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL

Enteropathy-Type Intestinal T-Cell Lymphoma Showing Jejunoileal Fistula: Report of a Case

Jejunoileal fistula is an extremely rare complication in patients with intestinal lymphoma. Here, we report a Japanese male patient with enteropathy-type intestinal T-cell lymphoma presenting abdominal pain and weight loss. A jejunoileal fistula was discovered during colonoscopy and pathological diagnosis was performed preoperatively by forceps biopsy. After elective surgery for partial resections of jejunum, ileum, and sigmoid colon, eight cycles of cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy led complete remission of the disease

Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia?lymphoma cells

Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target. This report first describes the effectiveness of a novel HSP90 inhibitor NVP-AUY922 to adult T-cell leukemia-lymphoma (ATL) cells

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors.

Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed