Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new cell line with megakaryoblastic features, designated UoC-M1, was established from the malignant cells of a 68-year-old patient with acute myeloid leukemia. The patient's leukemic cells reacted with alpha-naphthyl acetate esterase and acid phosphatase and expressed CD7, CD24, CD34, CD38, CD45, HLA-DR and CD61. Cytogenetic analysis of the patient's malignant cells (and of the UoC-M1 cells) showed a human, male hypodiploid karyotype with many chromosome rearrangements and marker chromosomes. Spectral karyotyping (SKY) analysis complemented the G-banded karyotyping and clarified several chromosomal translocations and identified the marker chromosomes. Fluorescence in situ hybridization (FISH) and SKY analysis demonstrated that one marker chromosome contained three segments of chromosome 9 interspersed with three segments of chromosome 11, as well as a portion of chromosome 19. FISH analysis with a probe for MLL revealed that the UoC-M1 cells contained four copies of the MLL gene. Southern blot analysis determined that the MLL gene had a germline profile while Northern and Western analyses showed that the MLL mRNAs and protein were of the appropriate sizes. This is the first report of amplification of the MLL gene which may be an additional mechanism of leukemogenesis or disease progression.
 ...
PMID:Establishment and characterization of a megakaryoblast cell line with amplification of MLL. 966 99

Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) and CALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes a src homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1 fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL.
 ...
PMID:ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). 969 99

Partial tandem duplication within the MLL gene has recently been described as a novel genetic alteration in acute myeloid leukemia (AML). It has been associated with trisomy of chromosome 11, but was also identified in AML patients with normal karyotypes. The current study was performed to investigate whether MLL duplications are restricted to AML, and hence whether they may also occur in normal hematopoietic cells. MLL-duplication transcripts were analyzed by nested reverse-transcriptase polymerase chain reaction (RT-PCR) in peripheral blood in two groups of 45 and 20 patients, respectively, as well as in two bone marrow samples from healthy volunteers. Duplications were detected in two independent nested RT-PCR experiments in the peripheral blood samples of 38 of 45 (84%) and 20 of 20 (100%) of the two groups and in both bone marrow samples. On this basis, MLL duplications seem to occur frequently in a subset of cells in normal hematopoiesis. The type of partially duplicated MLL transcripts varied substantially. Three transcripts were identical to those known from AML. In addition, four new transcripts were characterized. Three of these four were in frame and potentially translatable. MLL duplications were also detected by seminested genomic PCR with intron 9- and intron 1-specific primers in 20 of 20 peripheral blood samples studied, indicating that the duplications are genomically fixed at the DNA level and are not an RT-PCR artifact. In summary, MLL duplications are regularly generated by homologous ALU recombination in a small number of hematopoietic cells of most or even all healthy donors. These data suggest that MLL duplications are not implicated in the malignant transformation in AML, or alternatively, that only a few cells will acquire additional oncogenic mutations necessary to establish the malignant phenotype of AML.
 ...
PMID:Partial tandem duplications of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors. 971 2

The major established cause of acute myeloid leukemia (AML) in the young is cancer chemotherapy. There are two forms of treatment-related AML (t-AML). Each form has a de novo counterpart. Alkylating agents cause t-AML characterized by antecedent myelodysplasia, a mean latency period of 5-7 years and complete or partial deletion of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline NF-1 and p53 gene mutations and the GSTT1 null genotype may increase the risk. Epipodophyllotoxins and other DNA topoisomerase II inhibitors cause leukemias with translocations of the MLL gene at chromosome band 11q23 or, less often, t(8;21), t(3;21), inv(16), t(8;16), t(15;17) or t(9;22). The mean latency period is about 2 years. While most cases are of French-American-British (FAB) M4 or FAB M5 morphology, other FAB AML subtypes, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) occur. Between 2 and 12% of patients who receive epipodophyllotoxin have developed t-AML. There is no relationship with higher cumulative epipodophyllotoxin dose and genetic predisposition has not been identified, but weekly or twice-weekly schedules and preceding l-asparaginase administration may potentiate the risk. The translocation breakpoints in MLL are heterogeneously distributed within a breakpoint cluster region (bcr) and the MLL gene translocations involve one of many partner genes. DNA topoisomerase II cleavage assays demonstrate a correspondence between DNA topoisomerase II cleavage sites and the translocation breakpoints. DNA topoisomerase II catalyzes transient double-stranded DNA cleavage and rejoining. Epipodophyllotoxins form a complex with the DNA and DNA topoisomerase II, decrease DNA rejoining and cause chromosomal breakage. Furthermore, epipodophyllotoxin metabolism generates reactive oxygen species and hydroxyl radicals that could create abasic sites, potent position-specific enhancers of DNA topoisomerase II cleavage. One proposed mechanism for the translocations entails chromosomal breakage by DNA topoisomerase II and recombination of DNA free ends from different chromosomes through DNA repair. With few exceptions, treatment-related leukemias respond less well to either chemotherapy or bone marrow transplantation than their de novo counterparts, necessitating more innovative treatments, a better mechanistic understanding of the pathogenesis, and strategies for prevention.
 ...
PMID:Secondary leukemias induced by topoisomerase-targeted drugs. 974 98

The treatment of cancer with alkylating drugs or topoisomerase II inhibitors can be responsible for the development of myelodysplastic syndromes and acute myelogenous leukemia. Alkylating agents such as melphalan and cisplatinum mainly produce damages at chromosomes 5 and 7 whereas topoisomerase II inhibitors-induced lesions essentially affect chromosomes 11 and 21. Rearrangements of the MLL gene at band 11q23 are frequently observed in human de novo myeloid and lymphoid leukemia as well as in leukemia or myelodysplasia secondary to therapy with drugs targetting topoisomerase II such as the epipodophyllotoxins. A relationship between the treatment with etoposide on teniposide and the development of translocations of the MLL gene has been clearly evidenced. The potential molecular basis of the chromosomal rearrangements implicating topoisomerase II and its inhibitors are discussed. The chemical structure of the inhibitors, their mechanism of action and the genes targetted by these drugs are presented. DNA cleavages induced directly by topoisomerase II inhibitors or by the drug induced apoptotic cellular response are responsible for nonrandom chromosomal aberrations and contribute to leukemogenesis.
 ...
PMID:[Chromosome translocations and leukemias induced by inhibitors of topoisomerase II anticarcinogenic drugs]. 975 16

Partial-tandem duplication (PTD) of an internal portion of MLL occurs in some cases of acute myelogenous leukemia (AML) with trisomy 11 or a normal karyotype. This type of MLL rearrangement may be transcribed into an mRNA species that is capable of encoding a partially duplicated protein associated with leukemogenesis. However, although several kinds of oncogenes, especially MYC, are often amplified on double-minute chromosomes (dmins) in hematological malignancies, no amplification of MLL has been reported in AML. Here, we report the first documented case of a patient with AML whose leukemic cells exhibited amplification of MLL on dmins. Furthermore, in this patient, MLL was rearranged in a PTD manner, with in-frame fusion of exons 2 and 6.
 ...
PMID:Amplification on double-minute chromosomes and partial-tandem duplication of the MLL gene in leukemic cells of a patient with acute myelogenous leukemia. 979 May 9

Many chromosome abnormalities, especially translocations or inversions, are closely associated with a particular morphologic or phenotypic subtype of leukemia, lymphoma, or sarcoma. Cloning the genes at the breakpoints of these rearrangements has provided critical tools for more-precise diagnosis; in some cases the particular diagnosis has prognostic implications. In addition, many of the genes had not been previously identified; their discovery has had a major impact on our understanding of the molecular biology of cancer. One such gene is MLL (myeloid-lymphoid or mixed-lineage leukemia), which is located at chromosome band 11q23. This gene is involved in the 4;11 and 11;19 (p13.3) translocations in acute lymphoblastic leukemia and in the 6;11, 9;11, and 11;19 (p13.1) translocations in acute myeloblastic leukemia. It is also involved in most translocations in infants (under 1 year of age) with acute leukemia and in patients with acute leukemia who were previously treated with drugs that inhibit toposiomerase II. The target gene of MLL is unknown at present, but because of its homology to the trithorax gene in Drosophila, and based on experimental data from mice, it appears to be involved in maintaining the function of some of the homeobox genes. The development of cytogenetic and molecular probes for MLL rearrangements has confirmed that translocations involving MLL are associated with a very poor prognosis. Thus physicians can identify patients with MLL involvement and can institute treatment for these high-risk patients. An increasing understanding of MLL should lead to more-effective targeted therapy.
 ...
PMID:Seminars from the University of Minnesota. Chromosome translocations: dangerous liaisons. 979 94

The human myeloid-lymphoid leukemia gene, MLL (also called ALL-1, Htrx, or HRX ), maps to chromosomal band 11q23. MLL is involved in translocations that result in de novo acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), mixed lineage leukemia, and also in therapy AML (t-AML) and therapy ALL (t-ALL) resulting from treatment with DNA topoisomerase II (topo II) targeting drugs. MLL can recombine with more than 30 other chromosomal bands, of which 16 of the partner genes have been cloned. Breaks in MLL occur in an 8. 3-kb breakpoint cluster region (BCR) encompassing exons 5 through 11. We recently demonstrated that 75% of de novo patient breakpoints in MLL mapped in the centromeric half of the BCR between two scaffold-associated regions (SAR), whereas 75% of the t-AML patient breakpoints mapped to the telomeric half of the BCR within a strong SAR. We have mapped additional structural elements in the BCR. An in vivo DNA topo II cleavage site (induced with several different drugs that target topo II) mapped near exon 9 in three leukemia cell lines. A strong DNase I hypersensitive site (HS) also mapped near exon 9 in four leukemia cell lines, including two in which MLL was rearranged [a t(6;11) and a t(9;11)], and in two lymphoblastoid cell lines with normal MLL. Two of the leukemia cell lines also showed an in vivo topo II cleavage site. Our results suggest that the chromatin structure of the MLL BCR may influence the location of DNA breaks in both de novo and therapy-related leukemias. We propose that topo II is enriched in the MLL telomeric SAR and that it cleaves the DNase I HS site after treatment with topo II inhibitors. These events may be involved in recombination associated with t-AML/t-ALL breakpoints mapping in the MLL SAR.
 ...
PMID:An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. 980 73

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.
 ...
PMID:Phenotypic conversion from t(8;21) acute myeloid leukemia to MLL gene rearrangement-positive acute lymphoblastic leukemia. 984 25

The t(9;11)(p22;q23) is the most common chromosomal translocation in topoisomerase II inhibitor therapy-related acute myeloid leukemia (tAML). This translocation fuses the MLL and AF9 proto-oncogenes producing a novel chimeric protein. In order to gain insight into the mechanism generating the t(9;11) and to clarify the role topoisomerase II inhibition may play in that mechanism we have cloned and sequenced the breakpoints from four tAML patients with the t(9;11). This sequence analysis identifies topoisomerase II consensus binding sequences near or at the chromosome 11 and chromosome 9 breakpoints in all four patients. One patient also had the consensus binding sequence for the TRANSLIN DNA-binding protein at the 9p22 and 11q23 breakpoints. Our results further support a direct role for topoisomerase II in the genesis of these tAML translocations.
 ...
PMID:Cloning and sequence analysis of four t(9;11) therapy-related leukemia breakpoints. 984 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>