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)

ALL1, the human homologue of Drosophila trithorax, is directly involved in human acute leukemias associated with abnormalities at 11q23. Using the differential display method, we isolated a gene that is down-regulated in All1 double-knockout mouse embryonic stem (ES) cells. The gene, designated ARP1 (also termed RIEG, Ptx2, or Otlx2), is a member of a family of homeotic genes containing a short motif shared with several homeobox genes. Using a bacterially synthesized All1 polypeptide encompassing the AT-hook motifs, we identified a 0.5-kb ARP1 DNA fragment that preferentially bound to the polypeptide. Within this DNA, a region of approximately 100 bp was protected by the polypeptide from digestion with ExoIII and DNase I. Whole-mount in situ hybridization to early mouse embryos of 9.5-10.5 days indicated a complex pattern of Arp1 expression spatially overlapping with the expression of All1. Although the ARP1 gene is expressed strongly in bone marrow cells, no transcripts were detected in six leukemia cell lines with 11q23 translocations. These results suggest that ARP1 is up-regulated by the All1 protein, possibly through direct interaction with an upstream DNA sequence of the former. The results are also consistent with the suggestion that ALL1 chimeric proteins resulting from 11q23 abnormalities act in a dominant negative fashion.
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PMID:Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene. 953 79

We showed that arsenic inhibited the cell growth of four B-cell leukaemia cell lines of 11 various cell lines in vitro. In two of these four lines, KOCL44 and LyH7, apoptosis was identified by morphological and nucleosomal DNA fragmentation studies. Three of the four B-cell lines that were growth inhibited were acute infantile leukaemia with t(11;19)(q23;p13) translocations involving the MLL gene that encodes the transcriptional factor Drosophila trithorax. The arsenic-induced apoptosis in KOCL44 and LyH7 cells was found to be linked to caspases by Western blot and enzymological analyses. The amount of Bcl-2 was reduced during apoptosis in LyH7 as judged by Western blot analysis. We concluded that combined activation of the caspases and down-regulation of Bcl-2 could determine the fate of B-cell leukaemic cells in response to arsenic.
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PMID:Arsenic induces apoptosis in B-cell leukaemic cell lines in vitro: activation of caspases and down-regulation of Bcl-2 protein. 973 58

Infants with Down syndrome may develop a transient myeloproliferative disorder (TMD) with the features of acute leukemia but resolving in a spontaneous remission. Chromosomal aberrations in addition to trisomy 21 have only rarely been described. In many cases of infant acute leukemia band q23 of chromosome 11 is involved in nonrandom translocations, often resulting in a rearrangement of the ALL-1 (MLL, HRX, HTRX 1) gene. Generally, this translocation carries a bad prognosis. We describe two newborn girls with Down syndrome and TMD in whom the constitutional trisomy 21 was combined with an acquired abnormality of chromosome 11. During the TMD the morphological and immunologic features were consistent with those of megakaryoblastic leukemia. The chromosome 11 abnormalities were del(ll)(q23), but rearrangements of the ALL-1 gene were not found. Our patients had remissions that occurred spontaneously or after a mild chemotherapy. The important finding is that additional chromosomal changes may occur during TMD in Down syndrome. The fact that the abnormality was in region 11q23 raises the question of whether the risk for developing leukemia is increased under these conditions.
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PMID:Transient myeloproliferative disorder with 11q23 aberration in two neonates with Down syndrome. 976 Jan 53

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.
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PMID:Seminars from the University of Minnesota. Chromosome translocations: dangerous liaisons. 979 94

Genes involved in chromosomal translocations, associated with the formation of fusion proteins in leukemia, are modular in nature and regulatory in function. It is likely that they are involved in the initiation and maintenance of normal hematopoiesis. A conceptual model is proposed by which disruption of these different genes leads to the development of acute leukemia. Central to this model is the functional interaction between the mammalian trithorax and polycomb group protein complexes. Many of the genes identified in leukemia-associated translocations are likely upstream regulators, co-participators or downstream targets of these complexes. In the natural state, these proteins interact with each other to form multimeric higher-order structures, which sequentially regulate the development of the normal hematopoietic state, either through HOX gene expression or other less defined pathways. The novel interaction domains acquired by the chimaeric fusion products subvert normal cellular control mechanisms, which result in both a failure of cell maturation and activation of anti-apoptotic pathways. The mechanisms by which these translocation products are able to affect these processes are thought to lie at the level of chromatin-mediated transcriptional activation and/or repression. The stimuli for proliferation and development of clinically overt disease may require subsequent mutations in more than one oncogene or tumor suppressor gene, or both. A more comprehensive catalogue of mutation events in malignant cells is therefore required to understand the key regulatory networks that serve to maintain multipotentiality and in particular the modifications which initiate and coordinate commitment in differentiating hematopoietic cells. We propose a model in which common pathways for leukemogenesis lie along the cell cycle control of chromatin structure in terms of transcriptional activation or repression. A clearer understanding of this cascade will provide opportunities for the design and construction of novel biological agents that are able to restore normal regulatory mechanisms.
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PMID:Translocations, fusion genes, and acute leukemia. 989 79

Many chromosome abnormalities, especially translocations of 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 had a major impact on our understanding of the molecular biology of cancer. One such gene is MLL (myeloid-lymphoid or mixed lineage leukemia) located at chromosome band 11q23. The target gene(s) of MLL is unknown at present, but because of its homology to the trithorax gene in Drosophila as well as experimental data from mice, it appears to be involved in maintaining the function of some of the homeobox genes. Most genes involved in translocations have homologs in other organisms. Comparison of the functions of these genes in human cells with their function in other systems has enriched our understanding of their role in cell biology.
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PMID:The critical role of chromosome translocations in human leukemias. 992 89

Various hematopoietic malignant disorders have been shown to bear chromosome abnormalities of the 11q23 band, which can be rearranged with many different chromosomal regions in a wide variety of different leukemia subtypes. Several laboratories have identified a trithorax-related gene that is involved in most of the 11q23 abnormalities. Although some patterns and associations between the partner genes are beginning to emerge, it is not yet possible to frame a single unifying hypothesis for 11q23 leukaemic transformation. The aim of this review is to summarise the recent data concerning these 11q23 rearrangements and the understanding of their consequences.
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PMID:Molecular abnormalities in leukemia: the 11q23 story so far. 1002

We have identified a gene at chromosome band 19q13.1, which is closely related to MLL. MLL is located in a region of chromosome 11q23 that has partial synteny with chromosome 19q. We have named this gene at 19q13.1, MLL2. MLL2 encodes a protein that exhibits a high level of similarity to MLL over several important protein domains. MLL2 is also ubiquitously expressed among adult human tissues, as is MLL. MLL is a homologue of the Drosophila gene trithorax (trx), which encodes a regulator of homeotic gene expression. MLL is involved in chromosome rearrangements associated with leukemia in mammals. However, no MLL2 rearrangements associated with leukemia have been recorded.
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PMID:MLL2: A new mammalian member of the trx/MLL family of genes. 1040 30

One of the most common chromosomal abnormalities in acute leukemia is a reciprocal translocation involving the HRX gene (also called MLL, ALL-1, or HTRX) at chromosomal locus 11q23, resulting in the formation of HRX fusion proteins. Using the yeast two-hybrid system and human cell culture coimmunoprecipitation experiments, we show here that HRX proteins interact directly with the GADD34 protein. We have found that transfected cells overexpressing GADD34 display a significant increase in apoptosis after treatment with ionizing radiation, indicating that GADD34 expression not only correlates with apoptosis but also can enhance apoptosis. The amino-terminal third of the GADD34 protein was necessary for this observed increase in apoptosis. Furthermore, coexpression of three different HRX fusion proteins (HRX-ENL, HRX-AF9, and HRX-ELL) had an anti-apoptotic effect, abrogating GADD34-induced apoptosis. In contrast, expression of wild-type HRX gave rise to an increase in apoptosis. The difference observed here between wild-type HRX and the leukemic HRX fusion proteins suggests that inhibition of GADD34-mediated apoptosis may be important to leukemogenesis. We also show here that GADD34 binds the human SNF5/INI1 protein, a member of the SNF/SWI complex that can remodel chromatin and activate transcription. These studies demonstrate, for the first time, a gain of function for leukemic HRX fusion proteins compared to wild-type protein. We propose that the role of HRX fusion proteins as negative regulators of post-DNA-damage-induced apoptosis is important to leukemia progression.
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PMID:Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. 1049 Jun 42

The Mixed Lineage Leukemia (MLL) gene is commonly involved in translocations in infantile leukemia and is amplified in some cases of adult myeloid leukemia. A homolog of MLL denoted MLL2, which represents the second human homolog of the Drosophila trithorax gene, was characterized by assembling ESTs, the KIAA0304 cDNA clone, RT - PCR fragments and a new clone isolated from a cDNA phage library and compared to the available genomic sequence. The MLL2 gene maps to 19q13.1, a region of frequent rearrangement or amplification in solid tumors. MLL2 consists of an 8.5 - 9 kb transcript and spans 20 kb of genomic DNA. The predicted MLL2 protein possesses all of the major domains defined in MLL and the two genes have a similar genomic structure. We find that MLL2 is amplified in two of 14 pancreatic carcinoma cell lines and one of five glioblastoma cell lines and is a likely critical gene in 19q13.1 amplifications. It is also a candidate for chromosomal rearrangements involving this chromosome locus. MLL2 is one additional mammalian trithorax-group gene with involvement in human cancer.
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PMID:MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines. 1063 8


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