Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-15 (IL-15) is a 14-kDa glycoprotein belonging to the same four helix bundle-cytokine family as IL-2. Although the biological activity of IL-15 in vitro has been studied extensively, its physiological role is still obscure. The receptors for IL-15 and IL-2 consist of three subunits, an unique alpha chain and shared beta and gamma chains. Since beta and gamma chains transduce the signals from the receptors, both cytokines share similar biologic functions, although IL-15 and IL-2 do not have sequence homology. The alpha chains function to increase binding affinity for each cytokines. Adult T-cell leukemia (ATL) cells constitutively express the IL-2 receptor (IL-2R) alpha and expression is believed to be essential in the early stages of disease development. We have recently shown that ATL cells also express the complete form of IL-15R including the alpha chain, and that ATL cells proliferate in response to exogenous IL-15. Since the mRNA of IL-15 is ubiquitous and is detected in many tissues and cells, it is possible that IL-15R stimulation is involved in the development and progression of ATL. Here, we review recent studies on IL-15 and IL-15R and their association with ATL and other lymphoproliferative disorders.
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PMID:Pathological roles of interleukin-15 in adult T-cell leukemia. 1051 61

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer factors such as NF-kappaB and SRF, and also potently activates trascription of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of HTLV-I infected T cells through the above pathways induces polyclonal proliferation of the cells in vitro; Tax however may function only transiently in the immediate post-infection period following infection in vivo. The long latent period of 60 years from infection to onset of disease suggests other mechanisms for ATL oncogenesis. Recent studies suggest that the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These genetic events could be responsible for the different stages of ATL: smoldering, chronic, lymphoma, and acute type, p16 and p53 genes are important negative regulators of the cell cycle and are often found to be mutated in neoplasms. Recent studies including ours demonstrated a high frequency of alteration of these two genes in primary ATL cells. Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting that the alteration of these cell cycle regulatory genes may be related to progression from smoldering or chronic to acute or lymphoma type ATL. Tax may be involved in mutagenesis of these genes through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/lymphoma type. Once transformation occurs, activation of the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma type ATL cells.
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PMID:HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia. 1142 48

This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR beta chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.
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PMID:Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy. 1170 53

A 36-year-old woman was referred to our hospital because of leukocytosis in June 2000, and was admitted to our hospital and diagnosed as having adult T-cell leukemia/lymphoma (ATL; acute type). Complete remission was achieved with eight courses of CHOP therapy, but ATL relapsed and she was readmitted to our hospital in September 2001. Laboratory examination showed elevated levels of serum LDH and soluble IL-2 receptor, and hypercalcemia. CT examinations showed swelling of the abdominal lymph nodes and hepatosplenomegaly. CHOP therapy improved the symptoms, but recrudescence soon occurred. After two courses of salvage therapy which resulted in no remission, the patient received an allogeneic peripheral blood stem cell transplant (allo-PBSCT) from her HLA-matched sibling donor after preconditioning with BU + CY in January 31, 2002. Cyclosporin A (CsA) and short-term MTX were used to prevent GVHD. Bone marrow engraftment was prompt and acute GVHD was not found. Two months later, recurrence was seen in the form of subcutaneous tumors, but the tumors spontaneously disappeared following CsA withdrawal. At the time of writing, eight months after the transplant, remission has been maintained. A graft-versus-leukemia (GVL) effect may have been the curative action in this case.
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PMID:[Cyclosporin A withdrawal causes spontaneous remission of recurrent subcutaneous tumors after allogeneic peripheral blood stem cell transplantation for adult T-cell leukemia/lymphoma]. 1269 82

Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell leukemia virus I-infected individuals. Presently, there is no effective therapy for ATL. A murine model of ATL was produced by introducing leukemic cells (MET-1) from an ATL patient into nonobese diabetic/severe combined immunodeficient mice. The MET-1 cells are activated T cells that express CD2, CD3, CD4, CD25, CD122, and CD52. We evaluated the efficacy of Campath-1H (alemtuzumab; a humanized monoclonal antibody directed to CD52), alone and in combination with humanized anti-Tac (HAT) directed to CD25 (interleukin 2 receptor alpha) or with MEDI-507 directed to CD2. We observed that four weekly treatments with 4 mg/kg HAT significantly prolonged survival of MET-1-bearing mice. However, the survival of mice receiving 4 weeks of 4 mg/kg Campath-1H was significantly longer than that of the group receiving four weekly treatments with HAT (P < 0.001). Treatment with Campath-1H for 4 weeks led to a striking prolongation of the survival of MET-1 ATL-bearing mice that was comparable with that of tumor-free nontreated controls. Using Fc receptor (FcR) gamma(-/-) mice, we found that FcRgammas on polymorphonuclear leukocytes and monocytes are required for Campath-1H-mediated tumor killing in vivo. These results demonstrate that Campath-1H has therapeutic efficacy on ATL in vivo in that the life span of the Campath-1H treatment group was comparable with that of mice that did not receive a tumor or therapy. The main tumor killing mechanism with Campath-1H in vivo involves FcRgamma-containing receptors (e.g., FcRgammaIII) on polymorphonuclear leukocytes and macrophages that mediate antibody-dependent cellular cytotoxicity and/or trigger cross-linking induced apoptosis. This study provides support for a clinical trial of Campath-1H in the treatment of patients with T-cell leukemias and lymphomas.
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PMID:Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H. 1455 36

Adult T-cell leukemia (ATL) is an aggressive malignancy that is associated with human T-cell lymphotropic virus I (HTLV-I) infection. HTLV-I transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown. To further examine the cause of this signaling pathway deregulation, we measured mRNA and protein expression levels by real-time PCR and Western blots, respectively, of four negative regulators of the IL-2R signaling pathway including src homology 2 (SH2)-containing phosphatase (SHP1), cytokine-inducible (CIS) SH2-containing protein, suppressor of cytokine signaling-1 (SOCS1) and protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) in six HTLV-1 negative and seven HTLV-1 positive T-cell leukemia lines. The activation status of the JAK/STAT pathway was also examined. SHP1 mRNA and protein expression levels were selectively down regulated in all HTLV-1-infected transformed cell lines, while CIS, SOCS1, and PIAS3 protein expression were markedly but variably upregulated and the cells showed evidence of constitutive STAT3 activation. In acutely HTLV-1 infected primary CD4+ T-cells there was a gradual loss of SHP1 expression over 10 weeks in culture which correlated with progression from immortalization to transformation and loss of IL-2 dependence for growth. Two transformed cell lines that were established following HTLV-1 infection showed loss of SHP1 expression and overexpression of CIS, SOCS1, PIAS3. However, this overexpression was not adequate to block constitutive activation of the JAK/STAT pathway. Thus, multiple levels of IL-2 receptor signal deregulation are found in HTLV-1 transformed cells, which may be a result of early loss of SHP1 expression.
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PMID:Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells. 1463 83

A-51-year-old woman with a sixteen-year history of mixed connective tissue disease was admitted to the Kitasato University Hospital because of hypogastric pain in September 1999. Colonofiberscopy and computed tomography in the abdomen demonstrated thickening of the intestinal wall with a hemorrhagic ulcer in the terminal ileum. The histopathologic findings of the lesion revealed diffuse infiltration of atypical T-lymphocytes. The titers of anti-HTLV-I antibody and serum soluble IL-2 receptor were elevated. The diagnosis of adult T-cell leukemia/lymphoma (ATLL) infiltrating the terminal ileum was made. Combination chemotherapy including VEPA-M was undertaken, and resulted in a partial response. ATLL became refractory about June 2000. Flaccid paralysis, dysesthesia in the left lower limb and bladder-bowel disturbance emerged in a few days, July 2000. T2-weighed MRCT images demonstrated that a lesion with a high intensity signal was present in the spinal cord around Th 7. Flower-like cells were detected in the cerebrospinal fluid. Infiltration of ATLL into the thoracic cord was diagnosed. Administration of intrathecal methotrexate and prednisolone, systemic dexamethasone and local irradiation of 30 Gy improved the paralysis and the abnormal MRCT findings. Rehabilitation restored the patient's ability to walk.
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PMID:[Successful radiotherapy for the thoracic cord infiltration of adult T-cell leukemia/lymphoma]. 1468 74

Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Indoleamine 2,3-dioxygenase (IDO), the l-tryptophan (l-TRP)-degrading enzyme, plays a key role in the powerful immunomodulatory effects of several different types of immune cells. In this study, we investigated the IDO expression in ATLL cells and the effect of chemotherapy on IDO-initiating l-TRP catabolism in patients with ATLL. Serum l-kynurenine (l-KYN) concentrations, l-KYN/l-TRP ratio, and the level of IDO mRNA expression in ATLL cells were significantly increased in ATLL patients compared to those in healthy and HTLV-positive carrier subjects. On the other hand, l-TRP level was significantly decreased in ATLL patients compared to that in healthy subjects. In the immunohistochemical staining, IDO was strongly expressed in cytoplasm of ATLL cells. Interestingly, serum l-KYN as well as soluble IL-2 receptor concentrations was significantly reduced, and l-TRP concentrations were significantly increased after chemotherapy. These data provide evidence that IDO is highly expressed in ATLL cells, and that IDO-initiating l-TRP catabolism changes with chemotherapy.
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PMID:Indoleamine 2,3-dioxygenase is highly expressed in human adult T-cell leukemia/lymphoma and chemotherapy changes tryptophan catabolism in serum and reduced activity. 1863 41

A 66-year-old man, on thrice-weekly hemodialysis for 7 years, was referred to Chiba Cancer Center Hospital in August 2006 because of a left axillary tumor. Computed tomography revealed several enlarged lymph nodes assembling at the left axilla. The serum soluble IL-2 receptor was 47,500 U/mL, and HTLV-1 antibody was positive. His parents came from Kyushu. The pathological diagnosis was peripheral T-cell lymphoma, CD4(+). He was clinically diagnosed as having an adult T-cell leukemia/lymphoma, lymphoma type, and clinical stage II. Two courses of CHOP therapy were given to the patient, without any response. Because the patient had to undergo hemodialysis consistently, we preferred mild salvage therapy to more intensive treatment. Then, sobuzoxane (SBZ), 1,600 mg/day in two divided doses, was administered orally for 5 days. Soon thereafter, unexpectedly, the axillary tumor rapidly became small, resulting in disappearance four months later. SBZ therapy, 800 mg/day x 3 days, was continued at intervals of 7 to 8 weeks until October 2008. At the time of reporting, May 2009, the patient was well without recurrence of ATLL, and the remission has lasted 26 months or more. The reason why CHOP-resistant ATLL responded dramatically to SBZ alone is not clear, but the plasma concentration of the metabolite of SBZ was possibly very high because of renal failure. Another possibility is that hemodialysis removed the growth factor(s) or anti-apoptotic factor(s) derived from ATLL cells.
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PMID:[Adult T-cell leukemia/lymphoma in a patient on hemodialysis-resistance to CHOP, but unexpected effect and remission achieved by sobuzoxane alone]. 2015

Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.
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PMID:JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells. 2240 24


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