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

We report an interesting case of acute myelogenous leukemia (AML) in a Jehovah's Witness patient. A 61-year-old woman, a Jehovah's Witness, consulted our hospital because of continuous fever and refractory pharyngitis. The white blood cell count was increased with myeloblasts and monoblasts, both of which showed positivity for CD33. The level of WT1 messenger RNA (mRNA) in the bone marrow was 130,000 copies/microg RNA. The patient's diagnosis was AML (M4). Because complete remission (CR) was not obtained with 2 courses of chemotherapy consisting of acrarubicin and cytarabine, we tried gemtuzumab ozogamicin (GO) with informed consent. No major side effects appeared, and CR was obtained after 2 courses of GO, which decreased the WT1 mRNA level to 480 copies/microg RNA. The patient has been in CR for 6 months with ubenimex. This case suggests that GO can be one of the treatment options in similar situations, although it should be used with considerable care.
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PMID:Complete remission induced by gemtuzumab ozogamicin in a Jehovah's Witness patient with acute myelogenous leukemia. 1756 18

The wild-type Wilms tumor gene, WT1, is overexpressed in myelodysplastic syndrome (MDS) as well as acute myeloid leukemia. In a phase I clinical trial of biweekly vaccination with HLA-A*2402-restricted WT1 peptide for these malignancies, 2 patients with MDS developed severe leukocytopenia in association with a reduction in leukemic blast cells and levels of WT1 messenger RNA (mRNA) after only a single vaccination with 0.3 mg of WT1 peptide. These results indicated that the WT1-specific cytotoxic T-lymphocytes (CTLs) elicited by WT1 vaccination eradicated the WT1-expressing transformed stem or progenitor cells and that MDS patients with little normal hematopoiesis required a new strategy of WT1 vaccination to avoid severe leukocytopenia. We describe the first trial for a 57-year-old male patient with chronic myelomonocytic leukemia who was vaccinated biweekly with a small quantity (5 microg/body) of WT1 peptide. After the start of vaccination, the leukocyte and monocyte counts (13,780/microL and 1930/microL, respectively) gradually decreased to within the normal range in association with a reduction in the WT1 mRNA level. Simultaneously, the percentage of WT1-specific CTLs as measured by the HLA-WT1 tetramer assay increased. This case demonstrates for the first time that vaccination with as little as 5 microg of WT1 peptide can induce WT1-specific immune responses and resultant clinical responses.
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PMID:Clinical and immunologic responses to very low-dose vaccination with WT1 peptide (5 microg/body) in a patient with chronic myelomonocytic leukemia. 1756 20

Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.
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PMID:WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. 1785 29

Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify previously unrecognized expression changes that occur only in AML blasts. We were particularly interested in those genes with increased expression in AML, believing that these genes may be potential therapeutic targets. To test this hypothesis, we compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells (N = 18), unselected bone marrows (N = 10), and unselected peripheral bloods (N = 10). Twenty genes displayed AML-specific expression changes that were not found in the normal hematopoietic cells. Subsequent analyses using microarray data from 285 additional AML patients confirmed expression changes for 13 of the 20 genes. Seven genes (BIK, CCNA1, FUT4, IL3RA, HOMER3, JAG1, WT1) displayed increased expression in AML, while 6 genes (ALDHA1A, PELO, PLXNC1, PRUNE, SERPINB9, TRIB2) displayed decreased expression. Quantitative RT/PCR studies for the 7 over-expressed genes were performed in an independent set of 9 normal and 21 pediatric AML samples. All 7 over-expressed genes displayed an increased expression in the AML samples compared to normals. Three of the 7 over-expressed genes (WT1, CCNA1, and IL3RA) have already been linked to leukemogenesis and/or AML prognosis, while little is known about the role of the other 4 over-expressed genes in AML. Future studies will determine their potential role in leukemogenesis and their clinical significance.
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PMID:Identification of genes with abnormal expression changes in acute myeloid leukemia. 1791 43

Many mammalian genes contain overlapping antisense RNAs, but the functions and mechanisms of action of these transcripts are mostly unknown. WT1 is a well-characterized developmental gene that is mutated in Wilms' tumor (WT) and acute myeloid leukaemia (AML) and has an antisense transcript (WT1-AS), which we have previously found to regulate WT1 protein levels. In this study, we show that WT1-AS is present in multiple spliceoforms that are usually expressed in parallel with WT1 RNA in human and mouse tissues. We demonstrate that the expression of WT1-AS correlates with methylation of the antisense regulatory region (ARR) in WT1 intron 1, displaying imprinted monoallelic expression in normal kidney and loss of imprinting in WT. However, we find no evidence for imprinting of mouse Wt1-as. WT1-AS transcripts are exported into the cytoplasm and form heteroduplexes with WT1 mRNA in the overlapping region in WT1 exon 1. In AML, there is often abnormal splicing of WT1-AS, which may play a role in the development of this malignancy. These results show that WT1 encodes conserved antisense RNAs that may have an important regulatory role in WT1 expression via RNA:RNA interactions, and which can become deregulated by a variety of mechanisms in cancer.
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PMID:Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer. 1794 Jan 40

Secondary tumors and leukemias are major complications in Hodgkin lymphoma (HL). They likely arise from clonal selection of cells that have accumulated genomic lesions induced by chemo- and radiotherapy and may be further promoted by the loss of DNA repair and/or other pathways ensuring the fidelity of replicated DNA. To distinguish genomic imbalances associated with the development of acute myeloid leukemia (AML) in HL we used an array-based comparative genomic hybridization (aCGH) strategy on whole lymph node biopsies of HL patient. Genomic imbalances (amplifications and deletions) associated with AML outcome in 3 classic HL patients, at clinical diagnosis they exhibited a discrete individual variability. Three amplifications and 5 deletions were shared by all 3 patients. They involved AFM137XA11, a 9p11.2 pericentric region; FGFR1, the FGF receptor most frequently translocated in AML; PPARBP, a co-activator of nuclear receptors RARalpha, RXR and TRbeta1; AFM217YD10, a 17q25 telomeric region; FGR, an SRC2 kinase involved in cytokine production by NK and CD4+ NKT cells; GATA3, a Th2-specific transcription factor; TOP1, involved in DNA recombination and repair; WT1, a transcription factor involved in CD8+ T cell response against leukaemic blasts. Immunohistochemistry confirmed aCGH results and distinguished the distribution of either amplified or deleted gene products in neoplastic Reed Sternberg (RS) cells and non-neoplastic lymph node components.
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PMID:Genomic imbalances associated with secondary acute leukemias in Hodgkin lymphoma. 1798 26

Several studies have reported previously that acute myeloid leukemia (AML) may express WT1 detected by RT-PCR and/or Northern blotting. The diagnostic utility of WT1 expression in AML using immunohistochemistry has not been reported previously. Paraffin-embedded tissue sections from 55 AML, 12 acute lymphoblastic leukemia (ALL), and 10 normal bone marrow specimens were immunostained for WT1 (anti-N terminus antibody). 22/55 AML cases (40%) demonstrated nuclear immunopositivity for WT1, including 20/47 bone marrow trephines and 2/4 granulocytic sarcomas. All the ALL and normal bone marrow specimens were negative. A significant proportion of AML expresses nuclear immunostaining for WT1, a finding that has only been described previously in Wilms' tumor and desmoplastic small round cell tumor. This finding is important for the correct interpretation of immunohistochemical findings in the diagnosis of "small round cell" tumors of childhood, especially in cases of extramedullary deposits of AML, in which traditional myeloid markers may be negative.
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PMID:Immunohistochemical nuclear positivity for WT1 in childhood acute myeloid leukemia. 1807 34

The discovery of underlying genetic lesions helps to better understand the mechanisms of leukemogenesis and identify prognostic subgroups. Recent insights have allowed normal karyotype acute myeloid leukemia (AML) to be split into many molecular entities according to the genetic status of FLT3, NPM, CEBPA and MLL. Genome-wide single nucleotide polymorphism analysis was performed on 22 well-characterised AML patients with a normal karyotype. At the same time, microsatellite instability was investigated using a commonly used panel of polymorphic markers. Loss of heterozygosity (LOH) was found in 22.7% of cases without an associated copy number variation, suggesting that LOH represented an acquired partial uniparental disomy (aUPD) event. Three UPD+ cases harboured NPM mutations, associated with FLT3-ITD in two of them. An additional UPD patient had mutations both in CEBPA and in WT1. MSI was present at three loci in the three UPD+ cases (60%), whereas single locus MSI was present in three UPD- patients (17%). MSI involved the polymorphic PIG3 promoter in two UPD+ cases. It remains to be tested whether UPD and MSI association marks a common pathway of leukemogenesis.
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PMID:Uniparental disomy may be associated with microsatellite instability in acute myeloid leukemia (AML) with a normal karyotype. 1845 69

Compelling evidences indicate a key role for regulatory T cells (T(reg)) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of T(regs). We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402-restricted manner. Importantly, they recognized HLA-DRB1*04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4(+)CD25(+)Foxp3(+)GITR(+)CD127(-) T(reg) phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of T(regs) strongly inhibited the expansion of natural killer (NK), NK T, and CD8(+) T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8(+) T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201-restricted peptide in the presence of T(regs) strongly inhibited the induction of anti-WT1-126 CD8(+) CTL responses as evidenced by both very low cytotoxic activity and IFN-gamma production. Moreover, these T(reg) clones specifically produced granzyme B and selectively induced apoptosis in WT1-84-pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 interleukin-5(+)/granzyme B(+)/Foxp3(+) CD4(+) T(regs) in five of eight HLA-DR4(+) acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of T(regs) in cancer patients.
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PMID:The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy. 1867 60

In recent years, a number of somatically acquired mutational changes have been identified in patients with acute myeloid leukemia (AML). Most of these genetic alterations occur in AML exhibiting a normal karyotype, representing the largest cytogenetic subgroup (40%-50%) of AML. These molecular findings not only provide novel insights into the pathogenesis of AML but also are of clinical importance. In this review we will discuss the most relevant gene alterations, including NPM1 gene mutations, internal tandem duplications (ITD) or tyrosine kinase domain (TKD) mutations of the FLT3 gene, CEBPA gene mutations, and partial tandem duplications (PTD) of the MLL gene, as well as mutations in the NRAS and WT1 genes. In part, these gene mutations have emerged as important prognostic markers and they now allow us to dissect cytogenetically normal (CN)-AML in distinct prognostic subgroups. Furthermore, these mutant molecules represent potential targets for molecular therapies.
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PMID:Prognostic implications of gene mutations in acute myeloid leukemia with normal cytogenetics. 1869 85


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