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)

TREB5 (hXBP-1) protein is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and activates their transcription. TREB5 is a member of the CREB/ATF family, containing a basic amino acid region and leucine zipper structure (b-Zip structure). To characterize the key domain of TREB5 for transcriptional activation, mutational analysis was carried out. The C-terminal region of 148-221 amino acids was identified as an activation domain and was also active when fused to Gal4 DNA binding domain. This domain contains three unique regions rich in glutamic acid, glutamine, or serine/threonine and is active in both osteosarcoma (HOS) and T (Jurkat) cell lines. All of these three regions are essential; however, a part of the serine/threonine region was dispensable in Jurkat, but not in HOS cells. In addition to the activation domain, the N-terminal region showed activity in conjunction with the b-Zip structure, but not with the Gal4 DNA binding domain. Furthermore, this region showed activity in Jurkat cells, but not in HOS cells. These results suggest that TREB5 has two activational functions in transcription and may provide diversity in cell-type-specific transcriptional activation, possibly through dimerization with other b-Zip proteins and phosphorylation.
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PMID:Identification of transcriptional activation domain of TREB5, a CREB/ATF family protein that binds to HTLV-1 enhancer. 760 16

Microspectrofluorometry allows the analysis of fluorescent molecules such as anthracyclines in the nucleus of isolated living cells. Using this technique, we confirmed that the amount of doxorubicin or THP-doxorubicin incorporated into the nucleus was related to the resistant or sensitive character of K562 cells. It was then extended to the study of fresh leukemic cells and kinetic studies were performed allowing the calculation of the retention rate (RR) of anthracycline (THP-doxorubicin) into the cell nucleus. A reproducibility study confirmed the accuracy of the method. Blast cells collected in patients with acute myeloid (n = 22) or lymphoid (n = 8) leukemia, at diagnosis (n = 26), or in relapse (n = 4) have been studied. RR varied from 8 to 98% independently of the type of leukemia or the clinical status. RR did not correlate either with P-glycoprotein or with CD34 expression although this latter result should be confirmed on a higher number of subjects. Among 18 patients presenting with AML at diagnosis, 14 have been treated with intensive chemotherapy including anthracyclines; the only one who had resistant disease had the lowest RR value. In conclusion, the results obtained here show that microspectrofluorometry allows the performance of kinetic studies on fresh leukemic cells in order to quantify chemo-resistance phenomena related to drug transport.
Leukemia 1995 Aug
PMID:In vitro study of THP-doxorubicin retention in human leukemic cells using confocal laser microspectrofluorometry. 764 25

Transient myeloproliferative disorder (TMD) is an uncommon syndrome strongly associated with abnormalities of chromosome 21. Blast transient proliferation appears most frequently at neonatal age and usually resolves spontaneously in two or three months. Two patients, a girl and a boy, with neonatal onset of TMD are reported. They both presented trisomy 21 mosaicism according to bone marrow cytogenetic analysis. Patient 1, on one end of the spectrum, showed a "classic" benign course with rapid resolution and favorable outcome. Patient 2, on the other hand, had two blast outbursts both followed by spontaneous remissions. He failed to thrive and never reached a good general condition, dying at 5 months of age from a respiratory infectious complication. The necropsy showed generalized extramedullary hemopoiesis without evidence of bone marrow blast infiltration or myelofibrosis. TMD has some clinical and laboratory features that make it unique and distinguishable from true congenital leukemia with which it may be initially mistaken. It usually has a benign course followed by a favorable outcome. As trisomy 21 mosaicism may not have overt phenotypic stigmata, it is possible that many cases of TMD in these children may have a silent, non-detected course. We also conclude that a favorable outcome is not always to be expected in TMD.
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PMID:Transient myeloproliferative disorder associated with trisomy 21, a wide range syndrome: report of two cases with trisomy 21 mosaicism. 775 4

The experiments reported here continue the study of regulated drug sensitivity by extending the observations to anthracyclines. Previous work has shown that hydrocortisone (HC) protects AML blast stem cells from the lethal effects of cytosine arabinoside (ara-C) while retinoic acid (ATRA) increases ara-C sensitivity; further mechanisms of regulation of ara-C sensitivity might include increase or decrease in repair of sublethal damage. Anthracycline dose-response curves are characterized by an initial shoulder, followed by exponential decrease in survival with increasing dose. The shoulder portion of such curves may indicate the accumulation of sublethal damage. We used two assays to look for evidence of regulation of anthracycline sensitivity by HC or ATRA; the clonogenic assay for blast stem cells detects drug effects on this crucial population, but only after several days on incubation, during which time repair might occur. Measurements of nicks in DNA show damage in the bulk population of cells, but these can be detected very soon after exposure to drug. Both methods showed the HC protected cells in two continuous cell lines (OCI/AML-2 and OCI/AML-5) while ATRA made the cells more sensitive. Blast cells freshly-obtained from six AML patients were also tested. Both assays showed HC protection and ATRA sensitization in three populations. The clonogenic assay detected both effects in cells from a fourth patient; the nicked DNA assay confirmed both effects in a fifth patient, where the results of the clonogenic assay did not reach statistical significance. Neither ATRA nor HC influenced the sensitivity of blasts from a sixth patient; but these cells were highly resistant to drug. Kinetic studies showed that damage persisted longer after treatment with anthracyclines than with ara-C. OCI/AML-2 cells treated with HC before drug accumulated fewer cells with nicked DNA after daunorubicin (DNR). Cells exposed to ATRA after DNR showed increased toxicity in kinetic experiments. We conclude that sensitivity to anthracyclines may be regulated by ligands for steroid receptors. Furthermore, since growth factors do not regulate anthracyclines' sensitivity, different mechanisms may be operative for the action of ligands for cell surface receptors. Finally, we suggest that retinoic acid might be considered for inclusion in standard anthracycline/ara-C regimens for the treatment of AML.
Leukemia 1994 Dec
PMID:Regulation by retinoic acid and hydrocortisone of the anthracycline sensitivity of blast cells of acute myeloblastic leukemia. 780 96

The Wilms' tumor gene (wt-1) is expressed in the developing fetal kidney, gonads and in Wilms' tumors. Recently, the expression of wt-1 in leukemia-derived cell lines and cases of acute leukemias (AL) was reported. The present study was designed to investigate the potential of wt-1 as genetic marker for acute myelocytic leukemias (AML). Blast cells from 52 patients with AML, 14 patients in complete remission (CR) and four leukemic cell lines were examined for expression of wt-1 mRNA. Peripheral blood mononuclear cells (PBMNC) and bone marrow (BM) from 13 healthy persons were used as negative controls. RNA of the wt-1 gene was expressed in 41/52 (79%) patients with previously untreated AML. The majority of the 14 patients studied in CR lost wt-1 expression. In three out of the four patients in CR reappearance of wt-1 expression preceded relapse of the disease. In three of the four tested cell lines wt-1 specific transcription was demonstrated. No correlation to FAB classification, immunophenotype or response to treatment was found. Our experiments indicate wt-1 expression in the majority of AML, but not in bone marrow or PBMNC of healthy controls. Therefore, wt-1 expression may be associated with the presence of malignant blast cells and the analysis of wt-1 gene expression via PCR may be a sensitive method for the detection of leukemic blast cells.
Leukemia 1994 Dec
PMID:The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells. 780 2

The use of FISH as a complement to the conventional cytogenetic studies is of great help in attaining a better characterisation of the chromosome anomalies present in haematological malignancies, such as chromosome 7 monosomy. A study was carried out in three cases of acute non-lymphoblastic leukaemia and a myelodysplastic syndrome with chromosome 7 involvement, as shown by conventional cytogenetic studies. The Cocktail probe for chromosome 7 (DZ1, DZ2) was used (Oncor) in performing in situ hybridation. A monosomic cell line for chromosome 7, undetected by conventional techniques, was disclosed with this procedure in two of the cases. In the remaining two patients the monosomy of chromosome 7 was confirmed, although at percentages different from those attained with the conventional methods.
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PMID:[Interphasic in situ fluorescent hybridization (FISH) in 4 cases of myeloid neoplasias with chromosome 7 changes]. 785 98

Blast cells from up to 70% of patients with acute myeloblastic leukemia (AML) exhibit a variable degree of autonomous growth in vitro which is related to the production of autocrine growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Approximately 40% of AML blasts with autonomous growth have been reported to exhibit abnormalities of retinoblastoma (Rb) protein expression. As the Rb protein is a known transcriptional repressor of the IL-6 promoter, we have investigated the relationship between absence of Rb protein and cytokine gene expression in AML. Blasts from 28 patients were studied, 19 were Rb protein positive by Western blot and by flow cytometry for nuclear Rb protein; blasts from nine patients were Rb-negative. Of the 28 specimens tested by RT-PCR, 24 were positive for GM-CSF mRNA, 21 for IL-1 beta mRNA, and 14 for IL-6 mRNA. Only the expression of IL-6 was found to be significantly associated with loss of Rb protein expression (p < 0.02). The relationship between Rb protein and IL-6 expression was further studied by suppressing Rb protein expression with antisense oligonucleotides. In three out of seven blasts so treated, IL-6 mRNA was induced following antisense treatment whereas control sense oligonucleotides had no effect. Blasts from four patients which secreted high levels of IL-6 exhibited in vitro autonomous growth which could be partially suppressed by anti-IL-6. These results suggest that deletion of Rb protein expression is a mechanism that can dysregulate IL-6 expression in leukemic blasts and thus potentiate the autonomous growth of these cells.
Leukemia 1994 Nov
PMID:Absence of retinoblastoma protein expression results in autocrine production of interleukin-6 and promotes the autonomous growth of acute myeloid leukemia blast cells. 796 42

Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.
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PMID:P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia. 798 Oct 66

IGF-I has been reported to increase hematopoietic progenitor cell cloning efficiency. To investigate this phenomenon, we studied the IGF-I responsiveness of human marrow cells expressing IGF-I receptor (IGF-IR), a direct strategy not used previously. IGF-IR+ and control CD34+ marrow cells were isolated using immunoaffinity methods. Then, the cells were cloned in methylcellulose containing variable amounts of serum- and lineage-appropriate growth factors supplemented with recombinant human IGF-I. In contrast to CD34+ cells, IGF-IR+ cells never gave rise to CFU-Blast, CFU-Mix, CFU-GM, BFU-E, or CFU-E. To substantiate the suggestion that CD34+ and IGF-IR+ cells were distinct populations, we used reverse transcription PCR to detect IGF-I, EpO, and KIT receptor mRNAs in these cells. The mRNA phenotype of CD34+ cells was EpO (+), KIT (+), and IGF-IR (-), while IGF-IR+ cells were IGF-IR (+), EpO (-), and KIT (-). These results suggested that IGF-IR is either not expressed or expressed at low levels on normal hematopoietic progenitor cells. Functional significance of the latter possibility was tested by exposing CD34+ cells to IGF-IR antisense oligodeoxynucleotides. Colony formation was unaffected by oligodeoxynucleotide disruption of IGF-IR, suggesting that, even if expressed at low level, the receptor's functional significance was doubtful. Nevertheless, when cultured in the presence of IGF-I, IGF-IR+ cells elaborated an activity with mild BFU-E stimulatory effects. Accordingly, if IGF-I plays a role in hematopoietic colony formation, it is probably and results from stimulation of IGF-IR-positive ancillary cells to secrete growth factors. Studies carried out with human leukemia cells yielded similar results.
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PMID:A reappraisal of the role of insulin-like growth factor I in the regulation of human hematopoiesis. 804 Feb 73

The purpose of this paper was to ascertain whether results obtained in cell cultures of AML clonogenic blast cells would provide a useful model for a clinical regimen that combines fludarabine (F-ara-AMP) and cytosine arabinoside (ara-C). In the cultures the nucleoside F-ara-A was used. Blast cells from the continuous lines OCI/AML-2 and OCI/AML-3 were grown, either in methylcellulose to quantify clonogenic cells, or in suspension to measure self-renewal as reflected in changes in numbers of clonogenic cells. F-ara-A, like ara-C, was found to be more toxic to blast stem cells in suspension than in the clonogenic assay, indicating that F-ara-A might, in addition to general cytotoxicity, have some specific inhibitory effects on self-renewing stem cells. F-ara-A was less cytotoxic than ara-C; but, when F-ara-A was given before ara-C, synergism was seen at some F-ara-A doses, as manifested by increased ara-C cytotoxicity. In contrast, when ara-C was given before F-ara-A, protection was observed. Control experiments make it unlikely that this effect is related to changes in the cell cycle following ara-C exposure. We conclude that the cellular studies reported here confirm previous pharmacological data indicating that F-ara-A before ara-C increases the effectiveness of ara-C by increasing the accumulation of ara-CTP. However the present experiments show that the synergism between F-ara-A and ara-C is dependent on both dose and schedule.
Leukemia 1993 Jul
PMID:A cell culture model for the treatment of acute myeloblastic leukemia with fludarabine and cytosine arabinoside. 832 Oct 50


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