Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DLX gene family is a family of divergent homeobox genes which are related to the Drosophila distal-less (Dll) gene and has been reported to be expressed primarily in the forebrain and craniofacial structures. We have previously identified a new member of this family, DLX-7. We now report that this gene is expressed in normal hematopoietic cells and leukemia cell lines with erythroid characteristics. We used an antisense oligonucleotide targeted against the translation start site of DLX-7 mRNA to inhibit its expression in a human erythroleukemia cell line K562, which expresses DLX-7 at a high level. The antisense oligonucleotide efficiently reduced the DLX-7 mRNA, while control oligonucleotides, including a mutant oligonucleotide identical to the antisense sequence except for four nucleotide mismatches, had no effect on DLX-7 mRNA level. Inhibition of DLX-7 expression decreased the plating efficiency by approximately 70% compared with control. The antisense treatment caused apoptosis, as shown by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) method. Down-regulation of DLX-7 expression by antisense treatment was associated with a reduction in GATA-1 and c-myc mRNA levels. Thus, we conclude that DLX-7 is expressed in hematopoietic cells and that the inhibition of its expression results in the decreased levels of GATA-1 and c-myc genes, with an accompanying induction of apoptosis.
 ...
PMID:Inhibition of DLX-7 homeobox gene causes decreased expression of GATA-1 and c-myc genes and apoptosis. 909 78

There is now considerable evidence suggesting that alterations in the DNA methylating machinery play an important role in tumorigenesis and tumour progression. For example, focal hypermethylation and generalised genomic demethylation are features of many different types of neoplasms. It is thought that tumorigenesis and tumour progression may be caused by hypermethylation induced mutational events and silencing of genes which control cellular proliferation and/or demethylation induced reactivation of genes which may only be required during embryological development. Consequently, we have begun to investigate the role of DNA methylation and developmental genes in malignant lymphoproliferative diseases. Previously, in all cases of non-Hodgkins lymphoma and leukemia studied, we have shown that the myogenic developmental gene Myf-3 is abnormally hypermethylated. In this review we discuss the possible significance of these findings since in vitro studies suggest that Myf-3 may play an important role in control of the cell cycle and therefore lymphomagenesis. In vitro and in vivo evidence suggests that PAX genes may also have oncogenic potential. The PAX family of developmental genes are involved in cellular differentiation, proliferation and cell migration. Expression of PAX3 in particular is associated with cellular mobility. Our previous studies have indicated that alternate regional expression of PAX genes may be controlled by DNA methylation. Therefore, we have proposed that abnormal methylation profiles of PAX3 may be associated with neoplastic transformation and/or metastatic potential. Results thus far reveal that the paired box of PAX3 is abnormally hypermethylated and the homeobox abnormally hypomethylated in lymphomas and leukemias. These new findings are consistent with our postulate and support the idea that inappropriate methylation induced activation or inactivation of developmental genes such as Myf-3 and PAX3 play an important role in lymphomagenesis and disease progression and that inspection of the methylation status of other developmental genes is warranted.
 ...
PMID:DNA methylation and developmental genes in lymphomagenesis--more questions than answers? 915 51

The burgeoning number of articles concerning the role of HOX genes and hematopoiesis ensures that this will continue to be an area of very active research. It seems clear that HOX genes are expressed in stage- and lineage-specific patterns during early stages of hematopoietic development and differentiation. Several lines of evidence suggest that multiple genes of the HOXB (B2, B4, B6-B9), HOXC (C6, C8), and HOXA (A5) are involved in erythropoiesis. Similarly, a number of genes of the HOXA, HOXB, and HOXC appear to play a role in lymphoid cells. Furthermore, several genes, such as A9, A10, B3, B7, and B8, may control myelomonocytic differentiation. The question arises as to whether such a multiplicity of HOX genes reflects redundancy or indicates subtlety of the regulatory machinary. A similar complexity has been observed for hematopoietic cytokines, and the current view is that, although multiple molecules may have similar or overlapping effects, each factor has a specific function and regulatory combinations appear to play a critical role in controlling hematopoietic cell processes (99). One challenge for the future is to delineate in more detail the precise expression patterns of these genes in the many distinct subpopulations of blood cells and during fetal development. Overexpression of HOX genes in hematopoietic cells can dramatically perturb the differentiation of various cell lineages and can contribute to leukemogenesis. Future studies may involve the overexpression of alternatively spliced versions of different HOX genes or of truncated versions of HOX genes to ascertain the functional domains of the proteins that mediate the biologic effects. The findings in HOX knockout mice confirm a role for these genes in normal blood cell development. Further work in this area will require careful examination of fetal hematopoiesis and of animals bearing multiple HOX gene knockouts. Involvement of HOX genes in leukemia is just beginning to be appreciated. Establishing the true extent of HOX gene mutations in human disease will require strategies such as comparative genomic hybridization (100) and analysis of high density oligonucleotide arrays (101). The holy grail of homeobox work is to discover the physiologic processes and specific target genes regulated by HOX proteins. Given the broad range of tissues in which HOX genes are expressed, they would appear to be involved in very basic cellular processes, e.g., cell proliferation and death, adhesion, and migration, etc., rather than the direct regulation of tissue-specific genes. The search for target genes may be made easier by the further characterization of cooperative DNA binding between HOX proteins and other transcription factors. We speculate that HOX proteins do not behave as conventional transcriptional activators or inhibitors but rather may mark genes for potential future activation, i.e., they may establish competency to execute specific differentiation programs, with the actual activation being accomplished by transcriptional pathways triggered by exogenous signals. This proposed function may be an architectural one, involving changes in the conformation of DNA and/or altering interactions between DNA and histones, thus making areas of the genome more or less accessible to other protein factors (102). If this is the case, we may need to develop new assays to discern the molecular action of HOX proteins. The ease of manipulating the hematopoietic systems would appear to make it a very attractive model for explicating the general functions of this remarkable family of genes.
 ...
PMID:Effects of HOX homeobox genes in blood cell differentiation. 936 17

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.
 ...
PMID:Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene. 953 79

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

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.
 ...
PMID:The critical role of chromosome translocations in human leukemias. 992 89

Based on cytogenetic studies, non-random chromosomal translocations which involve the HOX11 gene at locus 10q24 and the TCR genes at loci 7q35 or 14q11 have been reported to occur in 5% of T-ALL. HOX11, a member of the homeobox family of genes, has been shown to play a role in T-ALL. The activation of the HOX11 gene by translocations to the TCR locus results in the inappropriate expression of a 2.3 kb transcript. In this paper we describe a t(10;14)(q24;q11) breakpoint from a T-ALL patient specimen. The breakpoint appears to be mediated by errors in the TCR/V(D)J recombination system, but is more complex than commonly described reciprocal translocations between the HOX11 and TCR genes, since it involves an inversion event of the TCRdelta genes. In addition, the breakpoint was characterised to a previously unsequenced area of the 10q24 locus, 3.4 kb upstream of the HOX11 gene. This breakpoint is more centromeric than the breakpoint cluster region previously shown to be involved in the majority of reported t(10;14)(q24;q11) translocations. Hence, our investigations of the translocation breakpoint in this patient identify another breakpoint region in the 10q24 locus and may define a novel recombination 'hot spot'. Surprisingly, our studies provide a mechanism for a previously unexplained complex translocation described by another group which involves the same region of the HOX11 promoter.
Leukemia 1999 Jun
PMID:Molecular characterization of a complex chromosomal translocation breakpoint t(10;14) including the HOX11 oncogene locus. 1036 Mar 88

In the last decade it has become clear that homeobox containing genes (HOX genes) not only play a significant role in regulating body formation, but in addition, they are contributing to organization and regulation of hematopoiesis. Modern molecular technologies showed that deregulated expression or disruption of Hox genes can lead to altered characteristics of blood cells or disturbance of blood cell development. In this paper we review the role of HOX proteins in hematopoiesis and leukemogenesis and speculate about their possible target genes and involvement in lymphomagenesis.
Leukemia 1999 Nov
PMID:The role of homeobox genes in normal hematopoiesis and hematological malignancies. 1055 39

Control of cell identity during development is specified in large part by the unique expression patterns of multiple homeobox-containing (Hox) genes in specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and Pc-G) proteins in Drosophila maintain Hox expression or repression, respectively. Mixed lineage leukemia (MLL) is frequently involved in chromosomal translocations associated with acute leukemia and is the one established mammalian homologue of Trx. Bmi-1 was first identified as a collaborator in c-myc-induced murine lymphomagenesis and is homologous to the Drosophila Pc-G member Posterior sex combs. Here, we note the axial-skeletal transformations and altered Hox expression patterns of Mll-deficient and Bmi-1-deficient mice were normalized when both Mll and Bmi-1 were deleted, demonstrating their antagonistic role in determining segmental identity. Embryonic fibroblasts from Mll-deficient compared with Bmi-1-deficient mice demonstrate reciprocal regulation of Hox genes as well as an integrated Hoxc8-lacZ reporter construct. Reexpression of MLL was able to overcome repression, rescuing expression of Hoxc8-lacZ in Mll-deficient cells. Consistent with this, MLL and BMI-I display discrete subnuclear colocalization. Although Drosophila Pc-G and Trx-G members have been shown to maintain a previously established transcriptional pattern, we demonstrate that MLL can also dynamically regulate a target Hox gene.
 ...
PMID:Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. 1058 12

There is increasing evidence that HOX homeobox genes play a role in leukemogenesis. Recent studies have demonstrated that enforced co-expression of HOXA9 and MEIS1 in murine marrow leads to rapid development of myeloid leukemia, and that these proteins exhibit cooperative DNA binding. However, it is unclear whether co-activation of HOXA9 and MEIS genes is a common occurrence in human leukemias. We surveyed expression of HOXA9 and MEIS1 in 24 leukemic cell lines and 80 patient samples, using RNase protection analyses and immunohistochemistry. We demonstrate that the expression of HOXA9 and MEIS1 in leukemia cells is uniquely myeloid, and that these genes are commonly co-expressed in myeloid cell lines and in samples of acute myelogenous leukemia (AML) of all subtypes except in promyelocytic leukemia. While HOXA9 is expressed in most cases of chronic myelogenous leukemia, MEIS1 is weakly expressed or not at all. Immunohistochemical staining of selected AML samples showed moderate to high levels of HOXA9 protein, primarily cytoplasmic, in leukemic myeloblasts, with weaker and primarily nuclear staining for MEIS1. These data support the concept that co-activation of HOXA9 and MEIS1 is a common event in AML, and may represent a common pathway of many different oncogenic mutations.
Leukemia 1999 Dec
PMID:Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. 1060 20


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