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)

TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
Mol Cell Biol 1996 Aug
PMID:Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. 875 9

Growth factors are commonly included in protocols for the treatment of acute myeloblastic leukemia (AML). Because the response of blast stem cells in culture to growth factors might influence the contribution of factor to clinical outcome, we studied 42 patients with AML or severe myelodysplasia. Peripheral blood blast cells were cultured in a clonogenic assay at three cell concentrations and with the following combinations of growth factors: no added growth factor (NF), G-CSF, GM-CSF, Kit ligand (KL), G-CSF + KL, GM-CSF + KL, and G-CSF + GM-CSF + KL. The slope of the line relating cell number plated to colony formation was calculated by least squares. The slopes were used to form three equally sized groups of patients. Marked heterogeneity was found in response of the blast populations to factor. A few general conclusions emerged: (1) autonomous blast populations are very rare; (2) although usually a population responds better to one of the growth factors than to others, seldom is the response exclusively to one factor; (3) when more than one factor is included in the cultures, synergism is usually seen. Significant associations were seen between successful remission induction for low slope values in cultures with NF or KL alone. For remission, but not survival, associations were found with intermediate values of slope in cultures with G-CSF + KL and GM-CSF + KL. We conclude that measurements of growth factor response are feasible and yield clinically useful data.
Hematopathol Mol Hematol 1996
PMID:Response of the blast stem cells of acute myeloblastic leukemia to G-CSF, GM-CSF, or the ligand for C-KIT, alone or in combination. 887 30

Multiple members of the A, B, and C clusters of Hox genes are expressed in hematopoietic cells. Several of these Hox genes have been found to display distinctive expression patterns, with genes located at the 3' side of the clusters being expressed at their highest levels in the most primitive subpopulation of human CD34+ bone marrow cells and genes located at the 5' end having a broader range of expression, with downregulation at later stages of hematopoietic differentiation. To explore if these patterns reflect different functional activities, we have retrovirally engineered the overexpression of a 5'-located gene, HOXA10, in murine bone marrow cells and demonstrate effects strikingly different from those induced by overexpression of a 3'-located gene, HOXB4. In contrast to HOXB4, which causes selective expansion of primitive hematopoietic cells without altering their differentiation, overexpression of HOXA10 profoundly perturbed myeloid and B-lymphoid differentiation. The bone marrow of mice reconstituted with HOXA10-transduced bone marrow cells contained in high frequency a unique progenitor cell with megakaryocytic colony-forming ability and was virtually devoid of unilineage macrophage and pre-B-lymphoid progenitor cells derived from the transduced cells. Moreover, and again in contrast to HOXB4, a significant proportion of HOXA10 mice developed a transplantable acute myeloid leukemia with a latency of 19 to 50 weeks. These results thus add to recognition of Hox genes as important regulators of hematopoiesis and provide important new evidence of Hox gene-specific functions that may correlate with their normal expression pattern.
Mol Cell Biol 1997 Jan
PMID:Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. 897 30

We describe two elderly male patients with acute myeloid leukemia transformed from myelodysplastic bone marrow. Neither patients had a history of prior exposure to mutagenic agents or other malignancies. Chromosome analysis at the time of initial diagnosis revealed 47,XY,del(5)(q14q33),+21 in patient 1 and 45,XY,add(1)(q23),-5,del(8)(p11.2p23),der(17)t(5;17)(p12;p11.2) in patient 2. In addition, numerous copies of double minute chromosomes were seen in both patients. We used fluorescence in situ hybridization to identify the amplified sequences presumed to represent the dmins in the leukemic cells. In both cases, it appeared that the dmins were derived from specific amplification of c-myc oncogene.
Hematopathol Mol Hematol 1996
PMID:Double minute chromosomes contain amplified c-myc oncogene sequences in acute myeloid leukemia. 904 62

An attempt was made to isolate resistant sublines of acute myelogenous leukemia (OCI/ AML-2) cells by chronic exposure to gradually increasing concentrations of daunorubicin in order to determine the mechanism of its resistance to this drug. Four daunorubicin-resistant sublines, AML-2/D100, /D250, /D500, and /D1,000 were isolated. The values of relative resistance of each daunorubicin-resistant AML subline were about 3, 6, 18, and 23-fold, respectively, as compared to the AML-2 line with an IC50 of 5 nM. The daunorubicin-resistant AML-2 sublines also showed cross resistance to various anticancer drugs including another anthracycline doxorubicin, a Vinca alkaloid vincristine, and an epipodophyllotoxin etoposide. A functional assay using flow cytometry showed decreased accumulation of daunorubicin in these sublines as compared to that of AML-2, which was reversed by cyclosporin A or cyanide. The development of the ATP-dependent multidrug resistant phenotype was due to low to high levels of expression of P-glycoprotein (PGP). The major mechanisms of increased PGP appears to be associated with gene amplification. In addition, other mechanisms such as increased stability of protein or mRNA might be involved depending on the concentration of daunorubicin used for selection. However, a multidrug resistance-associated protein (MRP) was not involved in these resistant sublines. These daunorubicin-resistant AML-2 sublines could provide a useful model for the study of multidrug resistance mediated by PGP.
Mol Cells 1997 Apr 30
PMID:Isolation and characterization of daunorubicin-resistant AML-2 sublines. 916 28

A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors (e.g., etoposide and doxorubicin). Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.
Mol Cell Biol 1997 Jul
PMID:DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. 919 42

A study was made to determine CR rate, response duration and survival in patients with RAEB or RAEB-t given AML-type chemotherapy, in particular the newer agents idarubicin and fludarabine. Eighty-five adults (58 RAEB-t, 27 RAEB) received either IA (idarubicin 12 mg/m2 daily on days 1-3, ara-C 1.5 g/m2 daily on days 1-4 CI), FA (fludarabine 30 mg/m2 daily on days 1-5, ara-C 2 g/m2 daily on days 1-5) or FLAG (FA + G-CSF 400 micrograms/m2 daily from day-1 until CR). IA was given exclusively to patients with better prognosis (as assessed by pretreatment karyotype), while FA and FLAG were given first to patients with worse and then to those with better prognosis. In remission, patients received lower doses of the same regimens for 6-12 months. The 85 patients comprise the largest reported series of RAEB or RAEB-t patients given AML-type chemotherapy. Their median age was 61 years, 33% had chromosome 5 or 7 abnormalities (-5/-7), and 55% were treated in laminar air flow rooms. The CR rate was 66%. While rates were highest in younger patients with a normal karyotype, CR rates in excess of 50% were also obtained in patients over age 60 (27/47; 57%) and in patients with -5/-7 (17/29; 59%). In 11 of the 14 cytogenetically abnormal patients in whom cytogenetic analysis was repeated at the time of CR, only normal metaphases were found. In the remaining 3 the number of abnormal metaphases was substantially reduced. However, the probability of continued CR was low (e.g. 452 +/- 0.08 at 12 months), and the only patients alive in CR beyond two years were patients under age 60 without -5/-7 and with RAEB-t. Survival probability was 0.35 +/- 0.05 at one year. Eight of 56 patients died in CR. While current AML-type chemotherapy can produce higher CR rates than is perhaps usually appreciated, in some patients with RAEB or RAEB-t (e.g. older patients with -5/-7) the brevity of the remissions and the risk entailed suggest that new post-remission therapies are needed to make this approach generally worthwhile.
Cytokines Mol Ther 1995 Mar
PMID:High remission rate, short remission duration in patients with refractory anemia with excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leukemia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF). 938 60

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.
Cytokines Mol Ther 1995 Jun
PMID:Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation. 938 68

Production of growth factors may provide a mechanism for disease evolution in some leukemias. Interleukin-1 is a plelotropic cytokine with the ability to synergize with other growth factors as well as to stimulate their production and release. Autocrine and/or paracrine secretion of interleukin-1 has been implicated in the pathogenesis of both chronic and acute myelogenous leukemia. Recently, a series of both specific and nonspecific IL-1 inhibitory molecules have been identified. These include IL-1 receptor antagonist, soluble IL-1 receptors, IL-1-converting enzyme inhibitor, IL-4, IL-10 and IL-1-antisense. Early experiments demonstrating the ability of some of these molecules to inhibit acute and chronic myelogenous leukemia growth suggest that clinical trials of these compounds may provide a novel management approach in these malignancies. Here we review the potential biologic and therapeutic role of IL-1 and its inhibitors in the myeloid leukemias.
Cytokines Mol Ther 1995 Sep
PMID:Interleukin-1 and its inhibitors: a biologic and therapeutic model for the role of growth regulatory factors in leukemias. 938 74

Fourteen poor risk acute myeloid leukemia (AML) patients were treated with G-CSF prior (from day 0) and during chemotherapy with fludarabine and Ara-C from day 1 to day 5 (the FLAG regimen). Several biological parameters were monitored on the blast population: multidrug resistance (MDR) functional expression by rhodamine-123 efflux (Rhd-E), cell cycle changes, induction of apoptosis and leukemic clonogenic cell growth (CFU-L). The mean basal Rhd-E value was 14.4% (range 0-51.2), and 12/14 patients exhibited a dye efflux > 4%, efficiently blocked by the MDR-reversal agent cyclosporin A. After 24 h of G-CSF administration, cell cycle studies showed in bone marrow (BM) samples a significant mean increase in S phase (p = 0.04) and in RNA content of G1 cells (p = 0.01), coupled to a significant increase in apoptosis (p = 0.02). Clonogenic cell growth analysis showed a twofold increase in BM CFU-L in 6 of the 14 cases tested. When G-CSF activity was assessed without the addition of exogenous growth factors (autonomous proliferation), a significant increase (p = 0.02) in CFU-L was found only in patients who achieved a complete remission (CR); these patients were also characterized by lower S-phase values at diagnosis. Eight of the 14 patients treated achieved CR, but the median response duration was three months, and only two cases are still in CR. The FLAG regimen can thus induce remission in poor risk AML patients. The responses, however, are short, suggesting that resistant cells are not efficiently affected by either the use of agents not involved in the MDR-efflux mechanism or by the G-CSF priming strategy. Other post-induction therapies need to be considered in further approaches.
Cytokines Mol Ther 1995 Dec
PMID:Multidrug resistance expression and proliferative studies in poor risk acute myeloid leukemia treated with the FLAG (G-CSF plus fludarabine and Ara-C) regimen. 938 83


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