Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC50) for Bcr-Abl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro.
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PMID:Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. 1565 98

The tyrosine kinase inhibitor imatinib inhibits the activity of the bcr/abl fusion protein present in patients with chronic myeloid leukemia. Although in chronic phase patients response to therapy can be monitored by quantitative RT-PCR for bcr/abl mRNA transcripts, in advanced disease (accelerated phase or blast crisis) only few patients respond on a molecular level. We investigated Wilms tumor gene (WT1) and bcr/abl mRNA transcripts in 16 accelerated phase CML patients by quantitative real time PCR. In contrast to the bcr/abl mRNA levels the WT1 mRNA levels were indicative for hematologic relapse (n = 6) versus response (n = 10).
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PMID:Quantitative RT-PCR of Wilms tumor gene transcripts (WT1) for the molecular monitoring of patients with accelerated phase bcr/abl + CML. 1566 Dec 71

This study was conducted to determine the outcome of patients who develop a second neoplasm after radiotherapy (RT) for a childhood solid tumor. From 1956 to 1998, 429 children with a malignant solid tumor were treated at a single radiation oncology facility. The medical records and radiotherapy charts were reviewed to determine if the patient developed a secondary neoplasm after treatment for malignancy. Twenty-three (5.4%) patients developed a secondary neoplasm. There were 12 males and 11 females with a median age at RT of 6.6 years (range, 2 months to 20 years). There were 14 malignant neoplasms in 13 (3.0%) and 14 benign neoplasms in 11 patients (2.6%). The types of initial solid tumors treated with RT were Ewing sarcoma in 6, Wilms tumor in 6, medulloblastoma in 5, neuroblastoma in 3, and other in 3. Median RT dose was 45 Gy (range, 12.3 to 60 Gy) using 4 MV in 9, 1.25 MV in 8, 250 KV in 4, and 6 MV photons in 1 patient. One child was treated using 15-MeV electrons. Fourteen had chemotherapy. Median follow-up was 23.2 years (range, 5.3 to 44.4 years). For the 14 malignant neoplasms, the median time interval from initial tumor to second malignancy was 10.1 years. The 14 second malignant neoplasms (SMN) were osteosarcoma in 3, breast carcinoma in 2, melanoma in 2, malignant fibrous histiocytoma in 1, dermatofibrosarcoma in 1, leiomyosarcoma in 1, mucoepidermoid carcinoma in 1, colon cancer in 1, chronic myelogenous leukemia in 1, and basal cell carcinoma in 1. Ten of the 14 SMN (71%) were at the edge or inside the RT field. The 5- and 10-year overall survival rate after diagnosis of an SMN was 69.2%; it was 70% for children with a SMN at the edge or inside the RT field and 66.7% for those outside of the RT field. The 14 benign neoplasms appeared at a median time of 16.9 years and included cervical intraepithelial neoplasia in 3, osteochondroma in 3, thyroid adenoma in 1, duodenal adenoma in 1, lipoma in 1, cherry angioma in 1, uterine leiomyoma in 1, ovarian cystadenofibroma in 1, and giant cell tumor in 1. Only 5 (36%) of the 14 benign tumors occurred in the RT field, with osteochondroma being the most common. Of 189 deaths occurring in 429 patients, only 3 (1.6%) were secondary to radiation-induced malignancy. Not all SMN in children receiving RT occur in the irradiated field. More than two-thirds of children with a radiation-induced malignancy are alive 10 years after the diagnosis of a SMN.
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PMID:Secondary neoplasms after radiotherapy for a childhood solid tumor. 1580 94

Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540-548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer(+) cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer(+) CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-gamma accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients' memory T cells were specifically reactivated to become IFN-gamma-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease.
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PMID:Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy. 1594 30

Acute lymphoblastic leukaemia (ALL) responds well to chemotherapy and the majority of children and a significant proportion of adults are cured of their disease after primary therapy. However, a number of patients relapse and allogeneic transplantation following conditioning with chemotherapy and radiotherapy offers the possibility of long-term survival in a proportion of these patients. A significant number of patients with ALL develop disease that is refractory to further therapy. The infusion of unmodified donor lymphocytes (DLI) following relapse after allogeneic transplantation has been shown to be curative in patients with chronic myeloid leukaemia (CML). However, in ALL the success rate is much lower. The results of in vitro and limited in vivo studies suggest that it may be possible to manipulate lymphocytes from the transplant donor to produce cytotoxic T-lymphocytes (CTL) with increased effectiveness in killing patients' ALL cells. This may be done in a number of ways. For example, some strategies utilise the patients dendritic cells (DC) to present tumour antigens to donor lymphocytes and convert them into CTL either by pulsing DC taken in remission with ALL cells or lysate, fusing such 'normal' DC with ALL cells or using DC cultured from the patient's ALL cells. Other approaches include exploiting the expression of leukaemia-specific antigens such as the proteinase PR-3 or the zinc finger transcription factor Wilms tumour-1 protein (WT-1) to stimulate CTL responses. Alternatively, immunotherapeutic strategies might exploit differences in minor histocompatibility antigens such as HA-1 and HA-2 between donor and recipient. These are expressed solely on haemopoietic cells making them suitable targets for donor derived anti-leukaemic cells. In vivo studies to date suggest that educated T-cells may have a role to play in the treatment of relapsed and refractory ALL in the future.
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PMID:Immunotherapeutic strategies in acute lymphoblastic leukaemia relapsing after stem cell transplantation. 1627 19

Leukemias are common worldwide. Wilms' tumor1 (WT1) protein is highly expressed in leukemic blast cells of myeloid and lymphoid origin. Thus, WT1 mRNA serves as a tumor marker for leukemias detection and monitoring disease progression. Curcumin is well known for its anti-cancer property. The objective of this study was to investigate the effect of curcumin on WT1 gene expression in patient leukemic cells. The leukemic cells were collected from 70 childhood leukemia patients admitted at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand, in the period July 2003 to February 2005. There were 58 cases of acute lymphoblastic leukemia (ALL), 10 cases of acute myeloblastic leukemia (AML), and 2 cases of chronic myelocytic leukemia (CML). There were 41 males and 29 females ranging from 1 to 15 years old. Leukemic cells were cultured in the presence or absence of 10 mM curcumin for 48 h. WT1 mRNA levels were determined by RT-PCR. The result showed that curcumin reduced WT1 gene expression in the cells from 35 patients (50%). It affected the WT1 gene expression in 4 of 8 relapsed cases (50%), 12 of 24 cases of drug maintenance (50%), 7 of 16 cases of completed treatment (44%), and 12 of 22 cases of new patients (54%). The basal expression levels of WT1 gene in leukemic patient cells as compared to that of K562 cells were classified as low level (1-20%) in 6 of 20 cases (30%), medium level (21-60%) in 12 of 21 cases (57%), and high level (61-100%) in 17 of 23 cases (74%). In summary, curcumin decreased WT1 mRNA in patient leukemic cells. Thus, curcumin treatment may provide a lead for clinical treatment in leukemic patients in the future.
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PMID:Inhibitory effect of curcumin on WT1 gene expression in patient leukemic cells. 1649 48

Donor-derived cytotoxic T lymphocytes (CTL) that respond to tumor antigens emerge after hematopoietic stem cell transplantation (HSCT), particularly in association with the status of immune recovery. To analyze the frequency of CTL against PR1, PRAME and WT1 after HSCT, a tetramer-based analysis was performed in 97 samples taken from 35 patients (9 AML, 11 MDS, 2 CML, 4 ALL, 7 lymphoma and 2 renal cell carcinoma [RCC]) with the HLA-A02 phenotype. Regarding PR1, only 1 sample showed the presence of tetramer-positive cells (0.04%/lymphocyte). Similarly, in PRAME, only 10 of 97 samples were sporadically positive with low titers. For WT1, positive results were detected in 39 of 97 samples and 7 (2 CML, 1 ALL, 2 lymphoma and 2 RCC) patients clearly showed positive results more than once. On the basis of these results, we performed serial analyses of WT1-specific CTL during the clinical course in 2 patients with RCC, who underwent HSCT with a reduced-intensity regimen, to examine the precise correlation between the kinetics of CTL, the occurrence of GVHD and the observed clinical response. A higher positive rate for WT1-specific CTL and a correlation with the clinical response suggest that WT1 may be a useful antigen for a wider monitoring application.
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PMID:Monitoring of WT1-specific cytotoxic T lymphocytes after allogeneic hematopoietic stem cell transplantation. 1659 44

Previous studies demonstrated that interleukin-12 (IL-12) enhances the non-MHC-restricted cytotoxic activity of NK cells and facilitate specific allogeneic human cytotoxic T lymphocyte responses against fresh leukemia cells and cell lines. The Wilms' tumor gene, WT1 mRNA, has been used as a marker of minimal residual disease (MRD) for evaluating therapeutic efficacy of patients with leukemia or myelodysplastic syndrome (MDS). This study was aimed to investigate whether in vitro IL-12 can lower WT1 gene expression in peripheral blood monuclear cells (PBMNC) from patients with leukemia or MDS. PBMNC from these 30 patients and 5 healthy volunteers were cultured at 5 x 10(5) cells/ml alone with or without 100 units/ml of IL-12 for 3 days. WT1 mRNA was measured by competitive reverse transcription polymerase chain reaction (RT-PCR) since WT1 mRNA is considered as a marker of minimal residual disease (MRD) in leukemia and MDS. The results demonstrated that WT1 mRNA in PBMNC of 5 healthy volunteers was less than 10(3) copies/microg of total RNA. Following the 3-day IL-12 treatment, mean WT1 mRNA of PBMNC was reduced from 10(4.8) to 10(4.2) copies/microg of total RNA in 6 CML patients, from 10(5.4) to 10(4.8) copies/microg in 12 MDS patients and from 10(5.0) to 10(4.2) copies/microg in 5 AML patients in CR, but not reduced in 5 of 7 AML in non-CR. It is concluded that IL-12 significantly decrease the quantity of leukemia cells in PBMNC of most patients with MDS, CML and AML in CR. IL-12 may be of considerable benefit in the elimination of MRD in patients with hematological malignancies.
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PMID:WT1 gene expression lowered by IL-12 In vitro in peripheral blood mononuclear cells from patients with leukemia or myelodysplastic syndromes. 1680 Sep 30

Specific immunotherapies for patients with chronic myeloid leukemia (CML) might eliminate residual CML cells after therapy with imatinib or chemotherapy and might enhance a specific graft-versus-leukemia effect after allogeneic stem cell transplantation. Here, we investigated the mRNA expression and T-cell recognition of tumor-associated antigens or leukemia-associated antigens (LAAs) in 34 patients with CML. Several LAAs are expressed in CML and therefore are candidate structures for specific immunotherapies: bcr-abl (100%), G250 (24%), hTERT (53%), MPP11 (91%), NEWREN60 (94%), PRAME (62%), Proteinase3 (71%), RHAMM/CD168 (83%), and WT1 (53%), but not BAGE, MAGE-A1, SSX2, or NY-ESO-1. The frequency of mRNA expression of RHAMM/CD168, Proteinase3, and PRAME was higher in acceleration phase and blast crisis. In flow cytometry, CD34+ progenitor cells typed positive for HLA molecules but were deficient for CD40, CD80, CD83, and CD86. However, RHAMM/CD168 R3-peptide (ILSLELMKL)-specific T-cell responses in CML patients were demonstrated by ELISPOT analysis and specific lysis of RHAMM/CD168 R3-pulsed T2 cells and CD34+ CML cells in chromium-51 release assays. RHAMM-R3-specific T cells could be phenotyped as CD8+R3*tetramer+CD45RA+CCR7-CD27- early effector T cells by tetramer staining. Therefore, vaccination strategies inducing such RHAMM-R3-directed effector T cells might be a promising approach to enhance specific immune responses against CML cells.
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PMID:Chronic myeloid leukemia cells express tumor-associated antigens eliciting specific CD8+ T-cell responses and are lacking costimulatory molecules. 1715 68

Wild-type Wilms' tumor gene WT1 is expressed at a high level in hematopoietic malignancies including acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndromes, as well as in various kinds of solid cancers. Human cytotoxic T lymphocytes (CTLs), which could specifically lyse WT1-expressing tumor cells with HLA class I restriction, were generated in vitro. It was also demonstrated that mice immunized with the WT1 peptide rejected challenges by WT1-expressing cancer cells and survived with no signs of autoaggression to normal organs that physiologically expressed WT1. Furthermore, we and others detected IgM and IgG WT1 antibodies in patients with hematopoietic malignancies, indicating that the WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing, WT1-specific, cellular immune responses were elicited in these patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of these findings, we performed a phase I clinical trial of a WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that the WT1 peptide cancer vaccine had efficacy in the clinical setting because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of a tumor-associated-antigen (TAA)-derived cancer vaccine may be enhanced in combination with stronger adjuvants, helper peptide, molecular-target-based drugs, or some chemotherapy drugs, such as gemcitabine, which has been revealed to suppress regulatory T-cell function. In contrast, reduction of WT1 peptide dose may be needed for the treatment of patients with hematological stem cell diseases, because rapid and strong destruction of malignant cell-sustained hematopoiesis before recovery of normal hematopoiesis may lead to pancytopenia in these patients.
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PMID:WT1 peptide cancer vaccine for patients with hematopoietic malignancies and solid cancers. 1761 50


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