Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used polymerase chain reaction amplification of minisatellites sequences (33.6.3, G3, PMS51, YNZ22) and of a Y chromosome specific sequence (DYZ1) to document chimaerism in 50 patients. Indications for bone marrow transplantation (BMT) was acute leukemia (n = 23). Aplastic anemia (n = 18) and inherited newborn disease, SCID and familial hemophagocytic lymphohistiocytosis (n = 9). The method was informative in all cases. We were able to demonstrate engraftment in 23/23 leukemia patients, 15/18 in aplastic patients and 8/9 in the last group of patients. HLA mismatching BMT was significantly less efficient. Analysis with DYZ1 probe in case of sex mismatched. BMT revealed the frequency of host residual cells after Bott. Their detection in a 0.01-1% range does not seem to influence the outcome of the transplantation procedure.
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PMID:[Value of the analysis of cellular chimerism following bone marrow graft by amplification of minisatellite sequences or specific of the Y chromosome]. 761 63

The chromosomal breakpoint and fusion transcripts of the pre-B-leukaemia-derived SEM cell line carrying a reciprocal t(4;11)(q21;q23) translocation were analysed. The breakpoint from derivative chromosome der4 was cloned and sequenced. The crossover site was localized in intron 7 of the ALL-1 gene on chromosome 11q23 and in a large intron of the AF-4 (FEL) gene. RNA transcripts from both wild-type genes and both hybrid genes were detected by reverse transcriptase polymerase chain reaction (RT-PCR) assays. In addition, alternatively spliced mRNA species derived from the der4 chromosome were found. They were generated by using the exon 5' of the breakpoint on der4 as a common splice donor site and the 5' boundaries of exons 8 or 9 of the ALL-1 gene as alternative splice acceptor sites. The hypothesis is proposed that selective pressure operators to maintain the presence of both derivative chromosomes as important elements in the leukaemogenic process.
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PMID:Molecular analysis of the chromosomal breakpoint and fusion transcripts in the acute lymphoblastic SEM cell line with chromosomal translocation t(4;11). 779 49

The t(4;11)(q21;q23) characterizes a distinct clinical entity of childhood and adult acute lymphoblastic leukemia (ALL) with a pre-pre-B-phenotype, monocytoid features, coexpression of CD15 and/or CDw65 and a dismal prognosis. The molecular correlate of the t(4;11) has been identified as a fusion transcript of HRX, a gene on 11q23 with homology to drosophila trithorax gene, and FEL, a serine-proline-rich gene on 4q21 of unknown function. The aim of the current study was to establish a reverse transcription-polymerase chain reaction (RT-PCR) approach for the rapid and sensitive detection of the HRX-FEL fusion transcript associated with the t(4;11). For this purpose, two groups of patients were studied: group A comprised cases with cytogenetically proven t(4;11) including three infant and four adult pre-pre-B-ALL, as well as the two cell lines RS4;11 and MV4;11. Group B consisted of ten adult pre-pre-B-ALL with the identical phenotype, but without cytogenetic confirmation of t(4;11). Using primers complementary to HRX and FEL cDNA sequences 300 to 500 bp 5' and 3' of published breakpoints, respectively, specific amplification products were obtained in all nine cases of group A and in nine of the ten cases of group B. Three different types of fusion transcripts were identified by sequence analysis with HRX breakpoints at nucleotides 4086 and 4218 and FEL breakpoints at nucleotides 1413, 1416, and 1458. These data indicate that RT-PCR allows the detection of HRX-FEL fusion transcripts in the vast majority of cytogenetically proven and immunophenotypically suspected t(4;11) ALL. Hence, this technique may allow identification of a further subset of high risk ALL and may also be useful for the monitoring of minimal residual disease in t(4;11) ALL.
Leukemia 1994 Apr
PMID:Detection of HRX-FEL fusion transcripts in pre-pre-B-ALL with and without cytogenetic demonstration of t(4;11). 790 8

The prognosis for patients with familial hemophagocytic lymphohistiocytosis (FHL) is poor, but the survival of affected children has been markedly prolonged by treatment with the epipodophyllotoxin derivatives etoposide and teniposide and by bone marrow transplantation. Secondary malignancies following epipodophyllotoxin therapy, including myelodysplastic syndrome (MDS) and acute myelocytic leukemia (AML), have recently been reported. We describe a 9-year-old boy, treated with epipodophyllotoxins for FHL since he was 3 years old, who developed MDS. He was administered etoposide (cumulative doses of 6.9 g/m2 intravenously and 13.6 g/m2 orally) and teniposide (3.4 g/m2 intravenously), but no other systemic antineoplastic drugs. This is, to our knowledge, the first report of a child with FHL developing MDS or AML. Moreover, MDS or AML following administration of epipodophyllotoxins as the sole systemic chemotherapeutic drug has not been reported previously. Supportive treatments, including the use of immunomodulating drugs, may reduce the risk for secondary leukemia in patients with FHL.
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PMID:Myelodysplastic syndrome following epipodophyllotoxin therapy in familial hemophagocytic lymphohistiocytosis. 831 65

The chromosomal translocation, t(4;11)(q21;q23), is the most common type of 11q23 chromosomal abnormality, being highly prevalent in infant acute leukemias and associated with a poor prognosis. The t(4;11) results in the fusion of an 11q23 gene (MLL, HRX, Htrx-1, or ALL-1) and a 4q21 gene (AF-4 or FEL). To further evaluate the 4q21 gene and its role in t(4;11) acute leukemia, we have cloned a 38-kb genomic region and mapped exons of the AF-4 gene. The 4q21 breakpoints in 19 cases of t(4;11) acute leukemia were analyzed by Southern analysis and pulsed-field gels. Seventeen of the 19 cases had breakpoints on chromosome 4q21 that were scattered in this 38 kb region. Expression of the AF-4 gene was studied in a total of 28 various nonhematopoietic, hematopoietic, and t(4;11) leukemic cell lines. The AF-4 gene was expressed in all cell lines as a major and a minor transcript. In addition to the normal transcripts, two fusion transcripts from the derivative 11 and derivative 4 chromosomes were identified in all t(4;11) cell lines except B1, which had only the der(11) transcript. These findings suggest that the breakpoints on 4q21 cluster over a broader area than do the breakpoints in the 11q23 gene, and that der(11) encodes the fusion RNA found consistently in leukemia cells.
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PMID:The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia. 835 74

The most common chromosome abnormality among infants with acute lymphoblastic leukemia is a t(4;11)(q2l;q23) and patients with this 4;11 translocation have a very poor prognosis. This unique genetic rearrangement fuses the MLL/ALL-1/HRX-Htrx gene at 11q23 with the AF4/FEL gene at 4q21. The resulting chimeric mRNAs presumably encode chimeric proteins which contribute to the leukemogenic state. The AF4 gene remains poorly understood with an unknown function. In this report, we describe the cDNA sequence information from human placental tissue where AF4 mRNA is highly expressed. We identified six intron-exon boundaries in the AF4 genomic structure and discussed more than 30 AF4 cDNA sequence variations reported in the literature. In addition, we identified three overlapping genomic sequences in GenBank entitled the "interleukin growth hormone cluster on chromosome 5q31," which, when aligned and translated, had three regions that suggested homology to the predicted AF4 protein sequence (32% amino acid sequence identity over 314 amino acids, 43% over 63 amino acids, and 50% over 40 amino acids). Of interest, this same chromosome 5q31 region has also been implicated in MLL gene rearrangements in human leukemia.
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PMID:AF4/FEL, a gene involved in infant leukemia: sequence variations, gene structure, and possible homology with a genomic sequence on 5q31. 876 69

11q23 chromosome aberrations are frequently observed in infantile as well as therapy-related leukemias. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partner genes such as AF4/FEL, LTG9/AF9 and LTG19/ENL. The resulting chimeric mRNAs are fused in frame and have been predicted to encode leukemia-specific chimeric proteins. In the present study, we raised antibodies against MLL, LTG9 and LTG19 and demonstrated that MLL and chimeric MLL-LTG9 and MLL-LTG19 products are synthesized in vivo and are localized in the nuclei, using immunofluorescence and cell fractionation studies. The truncated N-terminal portion of the MLL product common to the various types of 11q23 translocation was also localized in the nuclei in a similar fashion. Murine 32Dc13 cells stably expressing the truncated N-terminal MLL protein exhibited an inhibition of differentiation and a growth advantage following stimulation by granulocyte-colony stimulating factor, although the IL-3 dependency was not significantly changed in comparison to the parental cells. These results suggest that the N-terminal portion common to various MLL-chimeric products plays an important role in leukemogenesis.
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PMID:Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation. 893 41

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disease with features similar to those of the murine motheaten phenotype resulting from mutations of protein tyrosine phosphatase SHP-1. This has raised the possibility that defects in SHP-1 or SHP-1-regulated signaling molecules may be present in FHLH. In this study, we examined SHP-1 protein and transcript in the peripheral blood mononuclear cells (PBMC) of an FHLH family. Our results show that the FHLH patient and the parents express comparable levels of a single SHP-1 protein and that the SHP-1 cDNA clone from the patient contains no mutation in the coding region. Interestingly, a reduced association of SHP-1 with the Jak family kinase Tyk2 was detected in the patient and the defect appears to have been inherited from one of the parents. This reduced SHP-1/Tyk2 association is likely due to a defect in Tyk2 or in cellular factors regulating Tyk2, because we found no abnormalities in SHP-1 or in SHP-1 association with the other Jak kinases. These data demonstrate that the SHP-1 gene is intact in FHLH and that the defect in some cases with this disease may involve signaling molecules regulated by SHP-1.
Leukemia 1998 Feb
PMID:Reduced Tyk2/SHP-1 interaction and lack of SHP-1 mutation in a kindred of familial hemophagocytic lymphohistiocytosis. 951 82

Acute leukemia with t(4;11)(q21,q23) translocation results from the in-frame fusion of the MLL to the AF4/FEL gene. In previous studies, we and others demonstrated that AF4 transcripts are present in a variety of hematopoietic and nonhematopoietic human cells. To further study the wild-type and leukemia fusion AF4, we used glutathione S-transferase (GST)-fusion proteins as immunogens to produce rabbit polyclonal antibodies that were specific for normal and chimeric AF4 proteins. Using Western blotting analysis, we demonstrated that the AF4 gene encodes proteins with apparent molecular weight of 125 and 145 kD. A 45-kD protein coprecipitated with AF4 protein in immunoprecipitation. Also, the anticipated MLL-AF4-encoded 240-kD protein was detected in all cell lines with t(4;11) translocations; fusion proteins were present in lesser quantity than the wild-type AF4. The proteins recognized by the antibodies are of the predicted sizes of the AF4 and MLL-AF4-encoded proteins based on previous DNA sequencing analysis. The MLL-AF4 fusion protein had a similar subcellular distribution as AF4. Both t(4;11) and non-t(4;11) leukemic cells showed a similar pattern of punctate nuclear staining in all cell lines tested using confocal immunofluorescence microscopy. AF4 antibodies should be useful for further elucidation of the function of AF4 in normal cellular physiology, as well as the function of MLL-AF4 in leukemogenesis. The antibodies should also be helpful for the diagnosis of the MLL-AF4 fusion proteins in t(4;11) leukemias.
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PMID:AF4 encodes a ubiquitous protein that in both native and MLL-AF4 fusion types localizes to subnuclear compartments. 980 77

Allogeneic bone marrow transplantation is limited by the availability of suitable HLA-matched donors and the risk of graft versus host disease (GvHD). In an attempt to overcome these limitations umbilical cord blood (UCB), has become a further alternative. UCB transplantations in Austria were started in 1991. As of September 31, 1998, six patients have been transplanted. Diagnoses were severe aplastic anaemia (SAA) (n = 2), acute lymphoblastic leukaemia (ALL) (n = 1), familial hemophagocytic syndrome (FHL) (n = 2) and chronic myelomonocytic leukaemia (CMML) (n = 1). Three patients received UCB grafts from HLA-identical siblings and three patients from unrelated donors, of whom two were disparate at two HLA loci (A/B) and one mismatched at one locus (C). Five patients were engrafted with complete donor hematopoiesis, with a median time of 26.5 days (range 14 to 39 days) to an ANC count of > or = 0.5 x 10(9)/L and a median time of 42.5 days (range 24 to 67 days) to a platelet count of > or = 20 x 10(9)/L. One patient with FHL had partial engraftment and died due to reactivation of cytomegalovirus (CMV) infection and CMV pneumonia on day +25. Of the five patients surviving the post-transplant period, one with CMML had a relapse on day +128 and died after a HLA-matched bone marrow transplantation from the same sibling donor in the second relapse. Another patient with ALL relapsed on day +200 but is still alive under palliative treatment; one patient with SAA showed graft rejection and autologous hematopoietic reconstitution and later had a successful CD34(+)-selected allogeneic peripheral stem cell transplant from a C-locus mismatched unrelated donor. Two patients (one with SAA and one with FHL) are alive with complete remission of the underlying disease. This report reflects the experience and results of UCB transplantation in Austria and discusses the position of UCB transplantation in the context of the other stem cell alternatives available today.
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PMID:Transplantation of related and unrelated umbilical cord blood stem cells in Austria. Austrian Working Party for Stem Cell Transplantation. Austrian Society of Hematology and Oncology. 1040 93


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