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)

Runx1/AML1 (also known as CBFA2 and PEBP23B) is a Runt family transcription factor critical for normal hematopoiesis. Runx1 forms a heterodimer with CBF3 and binds to the consensus PEBP2 sequence through the Runt domain. Runx1 enhances gene transcription by interacting with transcriptional coactivators such as p300 and CREB-binding protein. However, Runx1 can also suppress gene transcription by interacting with transcriptional corepressors, including mSin3A, TLE (mammalian homolog of Groucho), and histone deacetylases. Runx1 not only is critical for definitive hematopoiesis in the fetus but also is required for normal megakaryocytic maturation and T-lymphocyte and B-lymphocyte development in adult mice. Runx1 has been identified in leukemia-associated chromosomal translocations, including t(8;21) (Runx1-ETO/MTG8), t(16;21) (Runx1-MTG16), t(3;21) (Runx1-Evi1), t(12;21) (TEL-Runx1), and t(X;21) (Runx1-Fog2). The molecular mechanism of leukemogenesis by these fusion proteins is discussed. Various mutant mice expressing these fusion proteins have been created. However, expression of the fusion protein is not sufficient by itself to cause leukemia and likely requires additional events for leukemogenesis. Point mutations in a Runx1 allele cause haploinsufficiency and a biallelic null for Runx1, which are associated with familial platelet disorder with a propensity for acute myeloid leukemia (FPD/AML) and AML-M0, respectively. Thus, the correct protein structure and the precise dosage of Runx1 are essential for the maintenance of normal hematopoiesis.
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PMID:Runx1/AML1 in normal and abnormal hematopoiesis. 1610 53

The chromosomal translocation t(12; 22)(p13;q11) in human myeloid leukemia generates an MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein. This protein consists of N-terminal MN1 sequences, a transcriptional coactivator fused to C-terminal TEL sequences, an ETS (E26 transformation-specific) transcription factor. Enforced expression of MN1-TEL in multipotent hematopoietic progenitors in knock-in mice perturbed growth and differentiation of myeloid as well as lymphoid cells. Depending on obligatory secondary mutations, these mice developed T-cell lympholeukemia. Here we addressed the role of MN1-TEL in myeloid leukemogenesis using the same mouse model. Expression of MN1-TEL enhanced the growth of myeloid progenitors in an interleukin 3/stem cell factor (IL-3/SCF)-dependent manner in vitro whereas 10% of MN1-TEL-expressing mice developed altered myelopoiesis with severe anemia after long latency. Coexpression of MN1-TEL and IL-3, but not SCF, rapidly caused a fatal myeloproliferative disease rather than acute myeloid leukemia (AML). Because MN1-TEL+ AML patient cells overexpress HOXA9 (homeobox A9), we tested the effect of coexpression of MN1-TEL and HOXA9 in mice and found that 90% of MN1-TEL+/HOXA9+ mice developed AML much more rapidly than control HOXA9+ mice. Thus, the leukemogenic effect of MN1-TEL in our knock-in mice is pleiotropic, and the type of secondary mutation determines disease outcome.
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PMID:Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9. 1610 79

We previously identified TEL/ARG as a novel fusion transcript consisting of the oligomerization domain of TEL and the kinase domain of ARG, in a case of acute myeloid leukemia. We report here the existence of an alternatively spliced TEL/ARG transcript lacking part of a F-actin binding domain of ARG, and the phenotype of TEL/ARG expressing 293T cells. In 293T cells, both TEL/ARG forms co-localized with the cellular beta-actin and were associated with a morphologic change of the cells, consisting in cell rounding and detachment from the tissue culture plastic. We identified the Rho inhibitor p190RhoGAP, a critical regulator of cellular adhesion, as a target of the aberrant kinase.
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PMID:TEL/ARG induces cytoskeletal abnormalities in 293T cells. 1631 Mar 6

STAT5 is constitutively phosphorylated in leukemic cells in approximately 70% of acute myeloid leukemia (AML) patients. To identify kinase candidates potentially responsible for STAT5 phosphorylation, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) mass spectrometry to detect phosphoproteins in AML cell lines. We established TEL-ARG and BCR-ABL fusion proteins as the mechanism underlying STAT5 phosphorylation in HT-93 and KBM-3 cells, respectively. In addition, we identified a JAK2 pseudokinase domain mutation in HEL cells and using siRNA downregulation, established JAK2 as the kinase responsible for phosphorylating STAT5. This study illustrates the benefit of LC-MS/MS mass spectrometry and siRNA for the identification of novel targets and mutations.
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PMID:Phosphoproteomic analysis of AML cell lines identifies leukemic oncogenes. 1660 41

In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)-Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P = .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/AML1-negative patients (P = .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients.
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PMID:Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. 1649 9

The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1alpha-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein. Functional studies show that TEL-ARNT interacts with HIF1alpha and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1alpha/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34+ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.
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PMID:Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation. 1654 90

The t(7;12)(q36;p13) is a recurrent translocation involving the ETV6/TEL gene (12p13) and a heterogeneous breakpoint at 7q36. A fusion transcript between HLXB9 and ETV6 in AML with t(7;12) is occasionally found. To study the incidence of t(7;12) in infant and childhood acute leukemia, we screened 320 cases <36 months using FISH. Additionally, 28 pediatric cases >36 months with cytogenetic breakpoints at 12p and 7q were investigated. We studied the presence of an HXLB9-ETV6 fusion transcript and quantified the expression of various genes located in the 7q36 breakpoint region. In total, six AML patients carried the t(7;12) of which five were infants and one child of 18 months. Only one out of 99 infant ALL patients harbored the t(7;12). No t(7;12) was found in older children with AML or ALL. AML patients carrying a t(7;12) had a poor outcome with a 3-year EFS of 0%. A fusion of HLXB9 to ETV6 was found in four AML cases with t(7;12). The 7q36 genes NOM1, LMBR1, RNF32, and SHH were equally expressed among t(7;12)-positive AML versus t(7;12)-negative AML, t(7;12)-negative ALL, or normal bone marrow. However, the HLXB9 expression was highly increased in t(7;12)-positive cases, including those with an HLXB9-ETV6 fusion. We conclude that the t(7;12) is almost exclusively present in infant AML and covers 30% of infant AML, while it is extremely rare in infant ALL and older children. The t(7;12) is associated with a poor outcome and an ectopic expression of HLXB9 is commonly involved in this genetic subtype of leukemia.
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PMID:High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9. 1664 86

MN1-TEL is the product of the recurrent t(12;22)(p12;q11) associated with human myeloid malignancies. MN1-TEL functions as an activated transcription factor, exhibiting weak transforming activity in NIH3T3 fibroblasts that depends on the presence of a functional TEL DNA-binding domain, the N-terminal transactivating sequences of MN1 and C-terminal sequences of MN1. We determined the transforming activity of MN1-TEL in mouse bone marrow (BM) by using retroviral transfer. MN1-TEL-transduced BM showed increased self-renewal capacity of primitive progenitors in vitro, and prolonged in vitro culture of MN1-TEL-expressing BM produced immortalized myeloid, interleukin (IL)-3/stem cell factor-dependent cell lines with a primitive morphology. Transplantation of such cell lines into lethally irradiated mice rescued them from irradiation-induced death and resulted in the contribution of MN1-TEL-expressing cells to all hematopoietic lineages, underscoring the primitive nature of these cells and their capacity to differentiate in vivo. Three months after transplantation, all mice succumbed to promonocytic leukemia. Transplantation of freshly MN1-TEL-transduced BM into lethally irradiated mice also caused acute myeloid leukemia within 3 months of transplantation. We infer that MN1-TEL is a hematopoietic oncogene that stimulates the growth of hematopoietic cells, but depends on secondary mutations to cause leukemia in mice.
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PMID:MN1-TEL, the product of the t(12;22) in human myeloid leukemia, immortalizes murine myeloid cells and causes myeloid malignancy in mice. 1681 Jan 99

Contemporary treatment of acute leukemia requires the accurate assignment of patients at diagnosis to specific risk groups. To determine whether gene expression profiling could enhance risk assignment, we used oligonucleotide microarrays to analyze the pattern of genes expressed in leukemic blasts from 360 pediatric ALL patients and 130 pediatric AML patients. Our analysis demonstrates that the single platform of gene expression profiling can accurately identify the known prognostically important genetic subtypes of ALL, including T-ALL, E2A-PBX1, TEL-AML1, MLL rearrangements, BCR-abl, and hyperdiploid >50 chromosomes, and AML, including t(15;17)[PML-RARalpha], t(8;21)[AML1-ETO], inv(16)[CBFbeta-MYH11], MLL gene rearrangement, and cases with FAB-M7 morphology. In addition, within ALL, a novel subgroup was identified based on its unique expression profile. Examination of the gene expression signatures for the different genetic subtypes of acute leukemia provided important insights into the molecular pathology of these leukemias.
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PMID:Acute leukemia: subtype discovery and prediction of outcome by gene expression profiling. 1688 96

Recurring chromosome abnormalities are strongly associated with certain subtypes of leukemia, lymphoma and sarcomas. More recently, their potential involvement in carcinomas, i.e. prostate cancer, has been recognized. They are among the most important factors in determining disease prognosis, and in many cases, identification of these chromosome abnormalities is crucial in selecting appropriate treatment protocols. Chromosome translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The mechanisms that result in such chromosome translocations in leukemia and other cancers are largely unknown. Genomic breakpoints in all the common chromosome translocations in leukemia, including t(4;11), t(9;11), t(8;21), inv(16), t(15;17), t(12;21), t(1;19) and t(9;22), have been cloned. Genomic breakpoints tend to cluster in certain intronic regions of the relevant genes including MLL, AF4, AF9, AML1, ETO, CBFB, MYHI1, PML, RARA, TEL, E2A, PBX1, BCR and ABL. However, whereas the genomic breakpoints in MLL tend to cluster in the 5' portion of the 8.3 kb breakpoint cluster region (BCR) in de novo and adult patients and in the 3' portion in infant leukemia patients and t-AML patients, those in both the AML1 and ETO genes occur in the same clustered regions in both de novo and t-AML patients. These differences may reflect differences in the mechanisms involved in the formation of the translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites, DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRs in most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but not in the BCR gene. In addition, the BCRs in MLL, AML1 and ETO have the lowest free energy level for unwinding double strand DNA. Virtually all chromosome translocations in leukemia that have been analyzed to date show no consistent homologous sequences at the breakpoints, whereas a strong non-homologous end joining (NHEJ) repair signature exists at all of these chromosome translocation breakpoint junctions; this includes small deletions and duplications in each breakpoint, and micro-homologies and non-template insertions at genomic junctions of each chromosome translocation. Surprisingly, the size of these deletions and duplications in the same translocation is much larger in de novo leukemia than in therapy-related leukemia. We propose a non-homologous chromosome recombination model as one of the mechanisms that results in chromosome translocations in leukemia. The topo II cleavage sites at open chromatin regions (DNase I hypersensitive sites), SARs or the regions with low energy level are vulnerable to certain genotoxic or other agents and become the initial breakage sites, which are followed by an excision end joining repair process.
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PMID:Chromatin structural elements and chromosomal translocations in leukemia. 1689 85


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