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1.
Ann N Y Acad Sci ; 1106: 114-42, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17442773

ABSTRACT

Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34(+) cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five- to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBPalpha. The HOXA9 component of the NUP98-HOXA9 fusion protein was protected from cullin-4A-mediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34(+) cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the nuclear pore complex but formed intranuclear aggregation bodies. Analysis of NUP98 allelic expression in AML and myelodysplastic syndrome showed loss of heterozygosity observed in 29% of the former and 8% of the latter. This was associated with poor prognosis.


Subject(s)
Gene Expression Regulation, Neoplastic , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Nuclear Pore Complex Proteins/physiology , Alleles , Animals , Antigens, CD34/biosynthesis , Cell Nucleus/metabolism , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 7 , Humans , Loss of Heterozygosity , Mice , Mice, Inbred NOD , Mice, SCID , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism
3.
Eur J Hum Genet ; 12(5): 365-71, 2004 May.
Article in English | MEDLINE | ID: mdl-14735163

ABSTRACT

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.


Subject(s)
Adenomatous Polyposis Coli/genetics , Chromosomes, Human, Pair 1/genetics , Adenomatous Polyposis Coli/pathology , Adult , Age Factors , Aged , Chromosome Mapping , DNA Glycosylases/genetics , Family Health , Female , Genetic Linkage , Genetic Predisposition to Disease/genetics , Genotype , Humans , Lod Score , Male , Microsatellite Repeats , Middle Aged , Models, Genetic , Mutation , Pedigree , Penetrance , Phenotype , Switzerland
4.
Leukemia ; 16(1): 67-73, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11840265

ABSTRACT

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E. coli and its apoptosis-inducing ability was compared with the leucine-zipper containing TRAIL, LZ-TRAIL. Both variants of TRAIL had the same apoptosis-inducing ability. Clonogenic progenitor assays showed that His-TRAIL significantly reduced the number of myeloid colonies (CFU-GM) and clusters from patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). His-TRAIL had no negative effect on the number of CFU-GM colonies and clusters derived from bone marrow cells of AML patients in complete remission, and lymphoma patients without bone marrow involvement, as well as those derived from normal cord blood cells. Moreover, we found that normal human stem cells treated with high doses of His-TRAIL maintain a repopulating potential when transplanted into NOD/SCID mice. To conclude, our data document that TRAIL does not affect normal human hematopoiesis but suppresses the growth of early primary leukemia and myelodysplasia progenitors.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Growth Inhibitors/pharmacology , Leukemia, Myeloid/pathology , Membrane Glycoproteins/pharmacology , Myelodysplastic Syndromes/pathology , Myeloid Cells/drug effects , Neoplastic Stem Cells/drug effects , Peptide Fragments/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Acute Disease , Animals , Cell Differentiation/drug effects , Cells, Cultured/drug effects , Colony-Forming Units Assay , Drug Screening Assays, Antitumor , Graft Survival , HL-60 Cells/drug effects , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/drug effects , Humans , Jurkat Cells/drug effects , K562 Cells/drug effects , Leucine Zippers , Lymphoma, Non-Hodgkin/pathology , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Peptide Fragments/chemistry , Peptide Fragments/genetics , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/pharmacology , Tumor Cells, Cultured/drug effects , Tumor Necrosis Factor-alpha/chemistry , Tumor Necrosis Factor-alpha/genetics , Tumor Stem Cell Assay
5.
J Med Genet ; 36(4): 290-4, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10227395

ABSTRACT

Primary congenital glaucoma (PCG) is an autosomal recessive eye disease that occurs at an unusually high frequency in the ethnic isolate of Roms (Gypsies) in Slovakia. Recently, we linked the disease in this population to the GLC3A locus on 2p21. At this locus, mutations in the cytochrome P4501B1 (CYP1B1) gene have been identified as a molecular basis for this condition. Here, we report the results of CYP1B1 mutation screening of 43 PCG patients from 26 Slovak Rom families. A homozygous G-->A transition at nucleotide 1505 in the highly conserved region of exon 3 was detected in all families. This mutation results in the E387K substitution, which affects the conserved K helix region of the cytochrome P450 molecule. Determination of the CYP1B1 polymorphic background showed a common DNA haplotype in all patients, thus indicating that the E387K mutation in Roms has originated from a single ancestral mutational event. The Slovak Roms represent the first population in which PCG is found to result from a single mutation in the CYP1B1 gene, so that a founder effect is the most plausible explanation of its increased incidence. An ARMS-PCR assay has been developed for fast detection of this mutation, thus allowing direct DNA based prenatal diagnosis as well as gene carrier detection in this particular population. Screening of 158 healthy Roms identified 17 (10.8%) mutation carriers, indicating that the frequency of PCG in this population may be even higher than originally estimated.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/genetics , Glaucoma/congenital , Glaucoma/genetics , Chromosome Mapping , Cytochrome P-450 CYP1B1 , Humans , Polymorphism, Genetic/genetics , Polymorphism, Single-Stranded Conformational , Romania
6.
Cesk Slov Oftalmol ; 54(5): 281-8, 1998.
Article in Slovak | MEDLINE | ID: mdl-9818478

ABSTRACT

A PCR-based test has been developed that makes it possible to detect a G to A substitution in the cytochrome P4501B1 gene. This mutation brings about a substitution of glutamic acid to lysine in the cytochrome P4501B1 molecule, and has been shown to be responsible, in homozygous form, for a severe and prognostically unfavourable form of primary congenital glaucoma (PCG). This type of PCG has been previously demonstrated to be extremely frequent in the population of Gypsies (Roms) in Slovakia. In this study, all 33 PCG Gypsy patients examined were found homozygous for this particular mutation, and among 101 unrelated healthy screened subjects from the Gypsy ethnic community, almost 14% of mutation carriers were identified. The test sugesed here makes it possible to perform a direct DNA-based prenatal diagnosis of PCG in the families at risk, as well as to screen for gene carriers.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/genetics , Glaucoma/congenital , Glaucoma/genetics , Point Mutation , Polymerase Chain Reaction , Cytochrome P-450 CYP1B1 , Glaucoma/diagnosis , Glaucoma/ethnology , Humans , Prognosis , Roma , Slovakia/epidemiology
7.
Cesk Slov Oftalmol ; 54(5): 289-93, 1998.
Article in Slovak | MEDLINE | ID: mdl-9818479

ABSTRACT

The authors present the results of a 20-year follow-up of a group of 125 patients with primary congenital glaucoma. Based on 10 fundamentally different indicators they provided evidence of two clinical forms of primary congenital glaucoma depending on the ethnic origin and type of heredity. In Slovakia is found: a/autosomal recessive hereditary primary congenital glaucoma in the gypsy population with an identified gene locus GLC3A with a different clinical picture, severe course and unfavourable therapeutic results; b/multifactorial primary congenital glaucoma in the remaining population of Slovakia with different clinical parameters, a milder course and favourable therapeutic results.


Subject(s)
Glaucoma/congenital , Female , Glaucoma/diagnosis , Glaucoma/ethnology , Humans , Male , Slovakia/epidemiology
8.
Hum Hered ; 48(1): 30-3, 1998.
Article in English | MEDLINE | ID: mdl-9463798

ABSTRACT

The autosomal recessive form of primary congenital glaucoma (gene symbol GLC3) has been recently mapped to two different loci, GLC3A (at 2p21), and GLC3B (at 1p36), respectively, on families of Turkish and Saudi Arabian provenance. This disorder is known to occur with an extremely high incidence in Roms (Gypsies) in Slovakia. We performed a standard linkage analysis on a sample of 7 Slovak Gypsy families comprising 18 affected members, and found significant linkage with four STR markers from the chromosomal region of 2p21 (D2S1788, D2S1346, D2S2328, and D2S1356), without heterogeneity. This finding demonstrates that in the Rom population of Slovakia, primary congenital glaucoma is due to the locus GLC3A, and consequently, to the mutation(s) in the cytochrome P4501B1 gene, which has been recently identified as the principal cause of the disease. Roms represent the third population, in which the disorder has been mapped to GLC3A.


Subject(s)
Genes, Recessive , Genetic Linkage , Glaucoma/congenital , Chromosome Mapping , Chromosomes, Human, Pair 2 , Female , Glaucoma/genetics , Homozygote , Humans , Male , Pedigree , Roma , Slovakia
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