Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in cellular and molecular immunology have led to the characterization of leukemia-specific T-cell antigens and to the development of strategies for effective augmentation of T-cell immunity in leukemia patients. While several leukemia-related antigens have been identified, this review focuses on the Wilms' tumor 1 (WT1) antigen and the proteinase 3 (Pr3) antigen that are overexpressed in leukemic cells and are already being used in the clinical setting. Moreover, WT1 is also overexpressed in a vast number of nonhematological solid tumors, thereby expanding its use as a promising target for cancer vaccines. Examples of spontaneous immune responses against WT1 and Pr3 in leukemia patients are presented and the potential of WT1 and Pr3 for adoptive T-cell immunotherapy of leukemia is discussed. We also elaborate on the use of professional antigen-presenting cells loaded with mRNA encoding WT1 exploiting the advantage of broad HLA coverage for therapeutic vaccination purposes. Finally, the summarized data underscore the potential of WT1 for the manipulation of T-cell immunity in leukemia and in cancer in general, that will likely pave the way for the development of more effective and generic cancer vaccines.
Leukemia 2005 Nov
PMID:Antigen-specific cellular immunotherapy of leukemia. 1612 Dec 14

The product of Wilms' tumor gene 1 (WT1) is overexpressed in diverse human tumors, including leukemia, lung and breast cancer, and is often recognized by antibodies in the sera of patients with leukemia. Since WT1 encodes MHC class I-restricted peptides recognized by cytotoxic T lymphocytes (CTL), WT1 has been considered as a promising tumor-associated antigen (TAA) for developing anticancer immunotherapy. In order to carry out an effective peptide-based cancer immunotherapy, MHC class II-restricted epitope peptides that elicit anti-tumor CD4(+) helper T lymphocytes (HTL) will be needed. In this study, we analyzed HTL responses against WT1 antigen using HTL lines elicited by in vitro immunization of human lymphocytes with synthetic peptides predicted to serve as HTL epitopes derived from the sequence of WT1. Two peptides, WT1(124-138) and WT1(247-261), were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles. Here, we also demonstrate that both peptides-reactive HTL lines were capable of recognizing naturally processed antigens presented by dendritic cells pulsed with tumor lysates or directly by WT1+ tumor cells that express MHC class II molecules. Interestingly, the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine. Because HTL responses to TAA are known to be important for promoting long-lasting anti-tumor CTL responses, the newly described WT1 T-helper epitopes could provide a useful tool for designing powerful vaccines against WT1-expressing tumors.
...
PMID:Defining MHC class II T helper epitopes for WT1 tumor antigen. 1622 Mar 25

Transient myeloproliferative disorder (TMD) is found in 10% of newborns with Down syndrome (DS). Myeloid leukemia develops in 25% within the following 3 years. Little is known about markers predicting leukemia occurrence. We studied expression levels of the Wilms tumor gene (WT1) by real-time quantitative PCR (RQ-PCR) in peripheral blood of five infants with TMD. WT1 levels were elevated similar to findings in AML. Longitudinal studies showed normalization of the WT1 level in all patients except one who developed GATA1 mutated myeloid leukemia at 11 months of age. The lack of normalization of WT1 level may be a predictor of leukemia development and WT1 expression may be an attractive marker for monitoring of minimal residual disease.
...
PMID:WT1 gene expression in children with Down syndrome and transient myeloproliferative disorder. 1624 75

Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (P<0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (P<0.01) compared to patients with other or no chromosomal aberrations. Older children (> or =10 years) expressed higher WT1 levels than children under 10 years of age (P<0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) > or =50 x 10(9)/l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P=0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P=0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.
Leukemia 2006 Feb
PMID:Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. 1634 Oct 43

Although Wilm's Tuomor gene (WT1) was first identified as a tumor suppressor gene for Wilm's tumor, WT1 overexpression has been detected in different malignant cell types including leukemia. Increased expression of WT1 in acute leukemia is potentially used as a marker of minimal residual disease. However, the significance of the gene for multiple myeloma is still not clear. To determine the clinical relevance of WT1 expression in multiple myeloma, we examined the association of clinical parameters and WT1 expression in bone marrow for 17 newly diagnosed multiple myeloma patients. WT1 was assessed by real-time quantitative polymerase chain reaction (RQ-PCR) and calculated standardized WT1 expression level per 100 plasma cells in the bone marrow specimen as "corrected WT1". The expression of standardized WT1 and corrected WT1 in myeloma was 59 to 1,600 copies/microg RNA and 0.05 to 406.3 copies/microg RNA/100 plasma cells, respectively, lower than in leukemia. WT1 transcripts increased when clinical factors worsen, including the stage, amount of M protein, Hb, platelet count, blood urea nitrogen (BUN), creatinine, serum alkaline phosphatase (ALP), calcium, beta2-microglobulin, thymidine kinase activity (TK), and C-reactive protein (CRP). In conclusion, the expression level of WT1 could be an additional marker to the standard parameters considered in risk assessment for multiple myeloma.
...
PMID:WT1 expression level and clinical factors in multiple myeloma. 1647 22

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.
...
PMID:Inhibitory effect of curcumin on WT1 gene expression in patient leukemic cells. 1649 48

An important measure to ensure successful follow-up in patients with allogeneic stem cell transplant is to evaluate for engraftment. Recent studies have shown that detecting minimal residual disease is important in order to predict early clinical relapse. We followed 88 leukemic patients with pre- and posttransplant Wilms tumor gene (WT1) levels to predict relapse and variable number of tandem repeats (VNTR) for engraftment. We have found that high pretransplant WT1 levels correlated significantly with relapse in all patient groups, but more significantly in the acute nonlymphoblastic leukemia (ANLL) patients. Posttransplant WT1 level correlated with VNTR status such that low WT1 is associated invariably with VNTR of 100% donor origin, while high WT1 is associated with VNTR of 20%. The association is significant in all patients, specifically in ANLL patients. In this preliminary study, we demonstrate that patients harboring detectable levels of WT1 prior to stem cell transplant have a higher chance of relapse, and posttransplant WT1 and VNTR status appeared to be dependent parameters predicting relapse when present in the posttransplant period. By combining 2 highly sensitive molecular techniques, we have found that this combined technique provided us with a promising alternative for overcoming the limitations imposed by each separate procedure. More studies are necessary before we can come to any significant conclusions.
...
PMID:Correlation of minimal residual disease by assessing Wilms tumor gene expression and engraftment by variable number of tandem repeats in children with leukemia posthematopoietic stem cell transplantation. 1694 68

The PAXgene RNA blood collection tube is used for RNA of peripheral blood (PB) and the stability of PB RNA in this tube has already been reported. However, the stability of bone marrow blood (BM) RNA in the PAXgene tube is unknown. Thus, we examined the stability of BM RNA in the PAXgene tubes. BM from leukemia patients was collected into PAXgene and EDTA tubes and stored at 4 degrees C for 5 days. RNA isolated from both tubes was analyzed by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Porphobilinogen deaminase (PBGD) mRNA of BM (as high-expression mRNA) and Wilms tumor suppressor (WT1) mRNA of BM (as low-expression mRNA) and very low copies of major BCR-ABL mRNA (as minimal residual disease of leukemia) of leukemia of BM were quantified by a LightCycler system. RNA yield from the PAXgene tubes and the intensity of 28S rRNA bands on RNA electrophoresis showed a degradation trend. However, the intensity of 18S rRNA bands from the PAXgene tubes remained. The expression of PBGD and WT1 of BM in the PAXgene tubes did not decrease for 5 days. The very low copies of major BCR-ABL mRNA in the PAXgene tubes were detectable on day 5 but those in the EDTA tubes were not detectable. Therefore, the PAXgene tube can be used for BM samples in a quantitative RT-PCR of the fusion gene transcripts of leukemia.
...
PMID:Examination of stability of bone marrow blood RNA in the PAXgene tube. 1695 Jun 75

Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.
Leukemia 2006 Nov
PMID:Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein. 1699 Jul 79

Targeted immunotherapies require the identification and characterization of appropriate antigen structures. Initially, T-cell based cancer vaccines were designed for patients with solid tumors after the definition of suitable tumor-associated antigens. Several immunological and even clinical responses prompted researchers and clinicians to extend the spectrum of cancer vaccines towards hematologic malignancies such as acute myeloid leukemia (AML). Only 20-40% of all patients with AML achieve a disease-free survival of more than 5 years. The graft-versus-leukemia (GVL) effect observed after allogeneic stem cell transplantation and donor lymphocyte infusions strongly suggests that T lymphocytes play a major role in the rejection of leukemic cells. Therefore, immunotherapy directed against leukemia-associated antigens might elicit specific immune responses that could eliminate minimal residual disease after chemotherapy, or enhance the GVL effect after hematopoietic stem cell transplantation. This review summarizes hitherto identified and characterized LAA as targets for T-cell-based immunotherapies. Current clinical peptide vaccination trials targeting different epitopes of the Wilms' tumor gene 1 (WT1), the proteinase-3 derived epitope peptide (PR1) and the receptor for hyaluronic acid mediated motility (RHAMM/CD168)-derived epitope R3 are reviewed, and perspectives but also limitations of immunotherapeutic approaches for AML patients are discussed.
...
PMID:Cancer vaccines for patients with acute myeloid leukemia--definition of leukemia-associated antigens and current clinical protocols targeting these antigens. 1714 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---