Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe several recent advances in our understanding and treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) including the use of cytogenetics to classify these diseases and to identify therapies that are specific for the abnormalities. Cell lines have provided readily available and very relevant models to understand these diseases. The two clear successes include the use of retinoic acid for acute promyelocytic leukemia and tyrosine kinase inhibitors (e.g., imatinib) for chronic myelogenous leukemia. Very recent results suggest a particular activity of lenalidomide, an analogue of thalidomide, in MDS patients with deletions of the long arm of chromosome 5 (so-called 5q minus syndrome), and notable activity of azanucleoside DNA demethylating agents in MDS with loss of chromosome 7. However, for the vast majority of cytogenetic abnormalities found in AML/MDS, no specific therapies have been identified. The use of a variety of molecular biology techniques have identified a large number of genomic abnormalities; the challenge of the next several decades is to identify specific therapies for these molecular defects.
 ...
PMID:Advances in the treatment of acute myeloid leukemia: from chromosomal aberrations to biologically targeted therapy. 1861 31

AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p, and 7q, older age and fast progression of the disease with extremely poor prognosis. MLL has been shown to be overexpressed in cases with 11q amplification. However, in most of the cases, the amplified region is not restricted to the MLL locus. In this study, we investigated 19 patients with AML/MDS and MLL gain/amplification. By means of array CGH performed in 12 patients, we were able to delineate the minimal deleted regions within 5q and 17p and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to identify candidate genes within these regions. Notably, analysis of our data suggests a correlation of loss of 5q and 17p and expression of genes present in 11q23-25. Furthermore, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from several other types of AML.
 ...
PMID:AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes. 1930 56

Myelodysplastic syndromes (MDS) comprise a heterogenous group of clonal disorders of hematopoietic progenitors, showing genetic instability and in many cases progression to acute myeloid leukemia (AML). When MDS progress towards AML (AML/MDS), additional genetic lesions cause a block in differentiation and an accumulation of blast cells. Hence, both pathophysiologically and clinically the MDS and AML/MDS phases are distinguishable. Leukemia cell lines are key resources for modelling hematological malignancies. Characterization of these cell lines has provided a rich vein of insights into the mechanisms underlying malignant transformation. Some 31 cell lines have been described in the literature purportedly established from patients with MDS. However, a significant minority of these has proved false after DNA profiling which revealed their cross-contamination with older established leukemia cell lines. Most remaining ("authentic") MDS cell lines were established during the leukemic phase of the disease progression rather than during the MDS phase. Based on these data we have assigned the 31 candidate MDS cell lines to one of the three categories: (1) false (cross-contaminated) cell lines and non-malignant cell lines; (2) malignant cell lines established in the AML/MDS leukemic phase; and (3) apparently legitimate MDS cell lines established during the MDS phase. While MDS and AML/MDS cell lines both provide singular resources for modelling pathology, mining oncogenically modified macromolecules, and testing druggability, we contend these groups should be considered separately.
 ...
PMID:Many are called MDS cell lines: one is chosen. 1934 51

The aim of this study was to investigate the mechanism, susceptibility, (18)F-FDG positron emission computerized tomography ((18)F-FDG PET/CT) features and the treatment of therapy-related acute myeloid leukemia. One patient with NHL was affected with t-MDS after treatment and then progressed to t-AML. The clinical data including bone marrow cell morphology, flow cytometry, karyotype and PET/CT features were analyzed. The results showed that the primary treatment for NHL refers to varieties of cytotoxic drug such as cyclophosphamide-hydroxydaunomycin-oncovin-prednisone (CHOP) chemotherapy. The interval time from the chemotherapy of NHL to the occurrence of t-MDS was 105 months and t-MDS progressed to AML-M(2) in 2 months. Karyotype analysis results of t-MDS and t-AML were normal. (18)F-FDG PET indicated that the FDG uptake in the bone raised diffusely. The patient showed complete response after second-line therapy (CAG regiments). In conclusion, the occurrence of t-AML/MDS may be associated with the application of the cytotoxic chemotherapeutics. (18)F-FDG PET may be an indicator predicting the transformation of t-MDS to t-AML.
 ...
PMID:[Secondary acute myeloid leukemia complicated after treatment of non-Hodgkin's lymphoma]. 1954 2

We hypothesized that standardized systemic drug delivery would improve treatment safety and provide better leukemia control. We therefore developed an intravenous busulfan formulation and combined it with fludarabine instead of cyclophosphamide in preparation for allogeneic stem cell transplantation (alloSCT). We used a Bayesian method to compare the outcomes of 67 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received intravenous busulfan-cyclophosphamide (BuCy2) with 148 subsequent AML/MDS patients who received busulfan-fludarabine (Bu-Flu). The groups had comparable pretreatment characteristics, except that the Bu-Flu patients were older, more often had unrelated donors and had a shorter follow-up. A greatly improved outcome in the Bu-Flu group is unlikely to be explained by improved supportive care during this time period. Overall, the data support replacing BuCy2 with or without antithymocyte globulin (ATG) with Bu-Flu with or without rabbit-ATG for AML or MDS. We further suggest that the high level of safety and fast recovery from conditioning therapy-related side effects after the Bu-Flu regimen makes it a suitable platform technology for testing additional adjuncts for improved posttransplant immune recovery and long-term disease control in patients who are at high risk of rapidly recurrent disease after alloSCT. The extremely low one-year treatment-related mortality as well as high overall and event-free survival of patients in the Bu-Flu group indicate that it is time to revisit the value of alloSCT compared with conventional maintenance chemotherapy for patients in first complete remission of AML/MDS.
 ...
PMID:Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. 1956 6

The development of non-myeloablative and reduced-intensity conditioning regimens has enabled older or medically infirm patients with myeloid malignancies to be treated with allogeneic hematopoietic cell transplantation (HCT). The regimens are sufficiently immunosuppressive to allow engraftment of allogeneic cells and they rely largely on graft-versus-leukemia effects rather than high-dose cytotoxic therapy to eliminate malignant cells. Overall 2-5-year survivals after allogeneic HCT in older patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) have ranged from 25% to 64%. Outcomes were comparable for human leukocyte antigen-matched related and unrelated grafts. The best results were seen in patients transplanted in the first or second remission. Relapse and progressive disease continue to be problems, particularly in patients with large tumor burdens at the time of HCT. Reduction of the tumor burden before HCT with targeted therapy such as radiolabelled anti-CD45 antibody may improve the outcome. Despite still existing problems, early results in elderly patients with AML/MDS have been encouraging.
 ...
PMID:Reduced-intensity conditioning transplantation in myeloid malignancies. 1956 10

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.
 ...
PMID:Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. 1966 37

Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (>or=RAEB2), but not in low-risk MDS (<RAEB2), indicating that CTNNA1 methylation might be important in the transformation of MDS to AML. CTNNA1 expression was lowest in AML/MDS patients with CTNNA1 methylation, although reduced expression was found in some patients without promoter methylation. Repressive chromatin marks (H3K27me3) at the promoter were identified in CTNNA1-repressed AML cell lines and primary leukemias, with the most repressive state correlating with DNA methylation. These results suggest progressive, acquired epigenetic inactivation at CTNNA1, including histone modifications and promoter CpG methylation, as a component of leukemia progression in patients with both 5q- and non-5q- myeloid malignancies.
 ...
PMID:Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies. 1982 47

Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype-phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL-negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12-->1q32 in PV, 1q21-32-->1q32-44 in post-PV MF or PMF), deletions (e.g. 1p13-36-->pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21-25;p21.3-23), and other partner chromosomes involving 1q10/1p11 and 1q21-25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21-1q32 and 1p11-13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN.
 ...
PMID:Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype-phenotype associations. 2000 54

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.
 ...
PMID:Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia. 2006 92


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