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)

Cytokines are important regulators of acute myelogenous leukemia (AML) blast proliferation. For a subset of patients the AML blasts show constitutive cytokine secretion and can undergo autonomous proliferation in vitro, whereas for other patients the blasts are dependent on exogenous cytokines for proliferation. The capability of autocrine proliferation is an adverse prognostic factor in AML. The three cytokines interleukin (IL)-4, IL-10 and IL-13 modulate in vitro blast proliferation, but the final effect of each cytokine (enhancement/inhibition/no effect) depends on differences between individual patients as well as the presence of other exogenous cytokines. In contrast to these divergent effects on blast proliferation, all three cytokines inhibit constitutive in vitro cytokine secretion by AML blasts. Because of the divergent effects on blast proliferation, it seems less likely that clinical therapy with these cytokines can be used to directly modulate AML blast proliferation. However, their effects on normal immunocompetent cells (and possibly the antigen-presenting capacity of AML blasts) are easier to predict. Thus direct (therapy with exogenous IL-4, IL-10 or IL-13) or indirect (enhancement of endogenous release of IL-4, IL-10 or IL-13) modulation of these cytokine effects on immunocompetent cells may become a useful clinical approach for enhancement of antileukemic immune effects. Such a modulation of immune reactivity can be used either as in vivo patient therapy or as manipulation of stem cell grafts prior to transplantation.
Cytokines Cell Mol Ther 1998 Sep
PMID:IL-4, IL-10 and IL-13 in acute myelogenous leukemia. 982 44

Phenotypic conversion from acute myeloid leukemia (AML) to acute lymphoblastic leukemia (ALL) is rare. A 38-year-old man was initially diagnosed as having AML (FAB-M2) associated with the t(8;21)(q22;q22) chromosomal abnormality. The blasts showed myeloperoxidase (MPO) activity and CD13 antigen expression. He showed complete remission after standard chemotherapy for AML. However, the patient relapsed with blasts showing ALL morphology (FAB-L1), MPO negativity, and CD19 antigen expression 33 months after cessation of AML therapy. Cytogenetic analysis at relapse was unsuccessful. Molecular analysis of ALL blasts revealed immunoglobulin heavy-chain gene and MLL gene rearrangements but no AML1 gene. MLL gene rearrangement or the 11q23 chromosomal abnormality has been associated with therapy-related leukemia. The subsequent ALL in our patient may have been induced by the chemotherapy including daunorubicin, known as a topoisomerase II inhibitor.
Hematopathol Mol Hematol 1998
PMID:Phenotypic conversion from t(8;21) acute myeloid leukemia to MLL gene rearrangement-positive acute lymphoblastic leukemia. 984 25

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.
Mol Cell Biol 1999 Jan
PMID:CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. 985 99

Human recombinant CK2 subunits were incubated for different times with the two main cytosolic proteases m-calpain and 20 S proteasome. Both, m-calpain in a calcium dependent manner and the 20 S proteasome, were able to degrade CK2 subunits in vitro. In both cases, CK2alpha' was more resistant to these proteases than CK2alpha. When these proteases were assayed on the reconstituted (alpha2beta2 holoenzyme), a 37 kDa alpha-band, analogous to that observed in AML extracts, was generated which was resistant to further degradation. No degradation was observed when the 26 S proteasome was assayed on free subunits. Studies with CK2alpha deletion mutants showed that m-calpain and the 20 S proteasome acted on the C-terminus end of CK2alpha. These results pointed to cytosolic proteases as agents involved in the control of the amount of free CK2 subunits within the cell, which becomes evident when CK2 is overexpressed as in AML cells.
Mol Cell Biochem 1999 Jan
PMID:Multiple forms of protein kinase CK2 present in leukemic cells: in vitro study of its origin by proteolysis. 1009 13

The AML1 and ETS families of transcription factors play critical roles in hematopoiesis; AML1, and its non-DNA-binding heterodimer partner CBFbeta, are essential for the development of definitive hematopoiesis in mice, whereas the absence of certain ETS proteins creates specific defects in lymphopoiesis or myelopoiesis. The promoter activities of numerous genes expressed in hematopoietic cells are regulated by AML1 proteins or ETS proteins. MEF (for myeloid ELF-1-like factor) is a recently cloned ETS family member that, like AML1B, can strongly transactivate several of these promoters, which led us to examine whether MEF functionally or physically interacts with AML1 proteins. In this study, we demonstrate direct interactions between MEF and AML1 proteins, including the AML1/ETO fusion protein, in t(8;21)-positive acute myeloid leukemia (AML) cells. Using mutational analysis, we identified a novel ETS-interacting subdomain (EID) in the C-terminal portion of the Runt homology domain (RHD) in AML1 proteins and determined that the N-terminal region of MEF was responsible for its interaction with AML1. MEF and AML1B synergistically transactivated an interleukin 3 promoter reporter gene construct, yet the activating activity of MEF was abolished when MEF was coexpressed with AML1/ETO. The repression by AML1/ETO was independent of DNA binding but depended on its ability to interact with MEF, suggesting that AML1/ETO can repress genes not normally regulated by AML1 via protein-protein interactions. Interference with MEF function by AML1/ETO may lead to dysregulation of genes important for myeloid differentiation, thereby contributing to the pathogenesis of t(8;21) AML.
Mol Cell Biol 1999 May
PMID:Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias. 1020 87

The objectives of this review are to: (a) demonstrate that the male CBA/Ca mouse has several characteristics that make it an excellent animal for the study of leukemogenesis, (b) show that several of the genetic abnormalities observed in the male CBA/Ca mouse during the development of radiation induced acute myeloid leukemia (AML) are syntenic with those frequently detected in patients with myeloid disorders such as myelodysplastic syndrome and AML, (c) illustrate that leukemia-related chromosomal lesions are the indicators for high risk individuals.
Blood Cells Mol Dis 1999 Feb
PMID:Advantages of the CBA mouse in leukemogenesis research. 1034 12

In 1991, the FAB group published a proposal to designate acute leukemias with minimal signs of myeloid differentiation as AML-M0. This proposal was meant to offer a provisional basis for the study of immature myeloid forms, with the understanding that it was susceptible to changes and improvements with new information derived from the laboratory. Since then there have been a number of reports detailing the biological and clinical features of patients with AML-M0. In this article we review the laboratory data acquired from various sources and suggest a partial modification of diagnostic criteria.
Blood Cells Mol Dis 1999 Apr
PMID:AML-M0: a review of laboratory features and proposal of new diagnostic criteria. 1038 94

The multidrug resistance of cancer cells can be mediated by an overexpression of the human MDR1 and MRP genes, which encode the transmembrane efflux pumps, the 170 kDa P-glycoprotein (Pgp) and the 190 kDa multidrug resistance-associated protein (MRP), respectively. In this study, we investigate which protein is preferentially overexpressed in the function of doxorubicin concentrations in the acute myelogenous leukemia cell line (OCI/AML-2). Multidrug-resistant AML-2 sublines were isolated in doxorubicin concentrations of 20, 100, 250, and 500 ng/ml. MRP was at first expressed at low concentrations of less than 5 x IC50 (100 ng/ml) of doxorubicin followed by the overexpression of Pgp with concentrations of more than 12.5 x IC50 (250 ng/ml) of doxorubicin. In addition, it appeared that increased amounts of MRP and its mRNA in AML-2/DX20 and /DX100 decreased gradually in both AML-2/DX250 and /DX500 overexpressing Pgp. In conclusion, it is thought that the overexpression of MRP or Pgp is dependent upon drug concentrations. It could be implicated that the overexpression of MRP might be negatively related to that of Pgp.
Mol Cells 1999 Jun 30
PMID:Drug concentration-dependent expression of multidrug resistance-associated protein and P-glycoprotein in the doxorubicin-resistant acute myelogenous leukemia sublines. 1042 Sep 92

Etoposide (VP-16) is extensively used to treat cancer, yet its efficacy is calamitously associated with an increased risk of secondary acute myelogenous leukemia. The mechanisms for the extremely high susceptibility of myeloid stem cells to the leukemogenic effects of etoposide have not been elucidated. We propose a mechanism to account for the etoposide-induced secondary acute myelogenous leukemia and nutritional strategies to prevent this complication of etoposide therapy. We hypothesize that etoposide phenoxyl radicals (etoposide-O(.)) formed from etoposide by myeloperoxidase are responsible for its genotoxic effects in bone marrow progenitor cells, which contain constitutively high myeloperoxidase activity. Here, we used purified human myeloperoxidase, as well as human leukemia HL60 cells with high myeloperoxidase activity and provide evidence of the following. 1) Etoposide undergoes one-electron oxidation to etoposide-O(.) catalyzed by both purified myeloperoxidase and myeloperoxidase activity in HL60 cells; formation of etoposide-O(.)radicals is completely blocked by myeloperoxidase inhibitors, cyanide and azide. 2) Intracellular reductants, GSH and protein sulfhydryls (but not phospholipids), are involved in myeloperoxidase-catalyzed etoposide redox-cycling that oxidizes endogenous thiols; pretreatment of HL60 cells with a maleimide thiol reagent, ThioGlo1, prevents redox-cycling of etoposide-O(.) radicals and permits their direct electron paramagnetic resonance detection in cell homogenates. VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts. 3) Ascorbate directly reduces etoposide-O(.), thus competitively inhibiting etoposide-O(.)-induced thiol oxidation. Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone). 4) A vitamin E homolog, 2,2,5,7, 8-pentamethyl-6-hydroxychromane, a hindered phenolic compound whose phenoxyl radicals do not oxidize endogenous thiols, effectively competes with etoposide as a substrate for myeloperoxidase, thus preventing etoposide-O(.)-induced redox-cycling. We conclude that nutritional antioxidant strategies can be targeted at minimizing etoposide conversion to etoposide-O(.), thus minimizing the genotoxic effects of the radicals in bone marrow myelogenous progenitor cells, i.e., chemoprevention of etoposide-induced acute myelogenous leukemia.
Mol Pharmacol 1999 Sep
PMID:Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. 1046 37

Background: The Philadelphia chromosome (Ph), t(9;22)(q34;q11), is detected by karyotyping in a minority of patients with acute leukemia. Ph results in fusion of the c-abl oncogene on chromosome 9 with the breakpoint cluster region BCR gene on chromosome 22. The purpose of this study was to compare reverse trascriptase-polymerase chain reaction (RT-PCR) for BCR/abl fusion to cytogenetic methods for Ph detection in patients with acute leukemia. Methods and Results: Peripheral blood and bone marrow samples from cases of adult acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) were examined for Ph by RT-PCR, karyotyping, and fluorescence in situ hybridization (FISH). Using total cellular RNA and a single primer pair, cDNA was transcribed, amplified, electorphoresed, and probed for BCR/abl fusion. Patient cells and SUPB15 and K562 cell lines were used as breakpoint controls. Karyotyping was done by standard Giemsa banding. FISH was performed on bone marrow smears using digxigenin-labeled DNA probes for major and minor bcr breakpoints (corresponding to involvement of major bcr exons 2/3 and minor bcr exon 1, respectively) and biotin-labeled DNA probes for abl. Rhodamine-conjugated antidigoxigenin and fluorescein-conjugated avidin yielded red and green fluorescent signals, respectively. A total of 32 samples from patients with AML were studied, 20 from patients with de novo or relapsed AML and 12 from patients in remission. Five of 32 cases of AML (16%) were RT-PCR+/Ph+ all with major bcr breakpoints between exons 3 and 4. One of the 32 cases (3%) was RT-PCR+/Ph+; this case was the only positive remission sample. Of the four T-PCR+/Ph- cases, one showed t(2;17), one showed t(9;11), and two had a normal karyotype. FISH was done in three RT-PCR+ cases, yielding positive results with the major probe in two. A total of 22 samples from patients with ALL were studies, 15 from patients with de novo or relapsed ALL and seven from patient remission. Seven of 22 cases of ALL (32%) were RT-PCR+, four with major-bcr breakpoints between exons 3 and 4, and three with breakpoints in the minor-bcr. Two of the 22 (9%) cases were RT-PCR+/Ph+. Of the five RT-PCR+/Ph- cases, two showed a 22q- but lacked the typical Ph break on chromosome 9, 1 showed a 12p-, and two had a normal karyotype. FISH was performed in four RT-PCR+ cases, yielding positive results with the major probe in two cases and with the minor probe in two cases. Conclusions: RT-PCR is more sensitive than karyotyping, detecting masked Ph or translocations not found by cytogenetic analysis. FISH is a helpful adjunctive test when used to confirm BCR/abl fusion in RT-PCR+/Ph- cases.
Mol Diagn 1996 Dec
PMID:Detection of BCRabl in Acute Leukemia by Molecular and Cytogenetic Methods. 1046 77


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