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1.
Leukemia ; 18(6): 1108-14, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15085164

ABSTRACT

Chromosomal rearrangements involving 3q26 either due to inversion or translocation with various partner chromosomes are a recurrent finding in malignant myeloid disorders. Typically, these chromosome aberrations contribute to ectopic expression of or to the formation of fusion genes involving the EVI1 proto-oncogene. Chromosomal translocations involving the short arm of chromosome 2 (p15-p23) and the distal part of the long arm of chromosome 3 (q26-q27) are a rare but recurrent finding in patients with myeloid malignancies, and are assumed to be part of this spectrum of disorders. Thus far, however, these translocations have been poorly studied. Here, we present 21 new cases with myelodysplasia, acute myeloid leukemia or CML in blast crisis, which upon karyotyping showed the presence of a t(2;3). Furthermore, an extensive literature review disclosed 29 additional cases. Morphological, clinical and cytogenetic assessment revealed the typical hallmarks of 3q26/EVI1 rearrangements, that is, trilineage dysplasia and dysmegakaryopoiesis, poor prognosis and additional monosomy 7. Molecular cytogenetic analysis and PCR in selected samples indicated that in most cases the translocation indeed targets the EVI1 locus. Mapping of the chromosome 2 breakpoints confirmed the initially suspected cytogenetic breakpoint heterogeneity at the 2p arm.


Subject(s)
Chromosomes, Human, Pair 2 , Chromosomes, Human, Pair 3 , Leukemia, Myeloid/genetics , Leukemia, Myeloid/pathology , Translocation, Genetic , Acute Disease , Adult , Aged , Child , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Proto-Oncogene Mas
2.
Clin Endocrinol (Oxf) ; 55(4): 543-8, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11678839

ABSTRACT

Classic genetic rearrangements in papillary carcinoma of the thyroid involve the RET- or TRK proto-oncogenes. We report a novel chromosomal translocation t(3;5)(q12;p15.3), confirmed by fluorescence in situ hybridization, in a multifocal follicular variant of a papillary carcinoma of the thyroid in a 79-year-old woman, with skin metastases as a presenting symptom. Three years earlier, another cutaneous metastasis on her scalp was misdiagnosed as hidradenoma. Four tumour foci were recognized in the thyroid, two with a follicular variant of papillary carcinoma. To detect loss of heterozygosity, 14 chromosomes were investigated with 59 microsatellite markers. A clonal relationship was detected between the two foci of tumour in the thyroid gland containing follicular variant of papillary carcinoma and one of the skin lesions tested, all demonstrating loss of heterozygosity (LOH) in the same region of chromosome 22. Based on earlier reports, the low rate of LOH detected is in agreement with the diagnosis papillary carcinoma of the thyroid. Whole body scintigraphy performed after ablative therapy with radioiodine revealed multiple metastases in the lungs and skeleton. After repeated radioiodine therapy, thyroglobulin under thyroxine suppression became undetectable and post-therapeutic scintigraphy revealed important regression of metastases.


Subject(s)
Carcinoma, Papillary, Follicular/genetics , Chromosomes, Human, Pair 22 , Loss of Heterozygosity , Skin Neoplasms/secondary , Thyroid Neoplasms/genetics , Translocation, Genetic , Aged , Bone Neoplasms/genetics , Bone Neoplasms/radiotherapy , Bone Neoplasms/secondary , Carcinoma, Papillary, Follicular/radiotherapy , Carcinoma, Papillary, Follicular/secondary , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 5 , Female , Humans , In Situ Hybridization, Fluorescence , Iodine Radioisotopes/therapeutic use , Karyotyping , Lung Neoplasms/genetics , Lung Neoplasms/radiotherapy , Lung Neoplasms/secondary , Skin Neoplasms/genetics , Skin Neoplasms/radiotherapy , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/secondary
3.
Exp Hematol ; 29(3): 322-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11274760

ABSTRACT

OBJECTIVE: The aim of this study was to develop an animal model for human acute lymphoblastic leukemia (ALL) in which the kinetics and characteristics of leukemia can be sequentially monitored in individual mice. MATERIALS AND METHODS: NOD/SCID mice were inoculated intravenously with primary ALL. Progression of leukemia was monitored throughout the development of disease by determination of absolute leukemic cell counts (LCC) in peripheral blood. RESULTS: LCC as low as 10(4) leukemic cells/mL blood could be detected. ALL cells from 5 of 5 patients engrafted, and after identification of the first leukemic cells in peripheral blood, LCC increased exponentially. Leukemic cells showed specificity of homing to spleen and bone marrow, and LCC strongly correlated with the level of leukemic engraftment in these organs throughout disease progression, demonstrating that LCC are representative for overall leukemic burden. Cytogenetic analysis of leukemic cells recovered after six successive in vivo transfers revealed no major karyotypic changes as compared to primary cells, and selection of the dominant clones was observed. This selection process was reflected by an increase in the rate of leukemic progression as compared to the first inoculation, demonstrating the accuracy with which kinetics of leukemic progression can be studied by determination of LCC. CONCLUSIONS: This model is suitable for detailed studies of kinetics and characteristics of ALL in vivo, and it may be useful for monitoring effects of novel therapeutic regimens.


Subject(s)
Neoplasm Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adult , Animals , Blast Crisis/pathology , Chromosomes, Human/genetics , Chromosomes, Human/ultrastructure , Disease Progression , Female , Graft Survival , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemic Infiltration , Lymphoid Tissue/pathology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Models, Animal , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Translocation, Genetic , Transplantation, Heterologous
4.
Diagn Mol Pathol ; 10(4): 228-35, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11763313

ABSTRACT

Chondrosarcomas are malignant cartilaginous tumors. Most are located in the medullar cavity (central chondrosarcoma), and a minority develop in a preexisting osteochondroma (peripheral chondrosarcoma). The authors present karyotypes for 37 central, peripheral, juxtacortical, and dedifferentiated chondrosarcomas. Using loss of heterozygosity (LOH) analysis and DNA flow cytometry, the authors previously showed that central and peripheral chondrosarcomas probably evolve by different genetic mechanisms. Peripheral chondrosarcoma is characterized by genetic instability, as was previously shown by a high percentage of LOH and a broad range in DNA ploidy. The authors now show that all peripheral chondrosarcomas tested are aneuploid, combined with many nonspecific chromosomal aberrations. Two juxtacortical chondrosarcomas showed normal chromosome numbers combined with limited structural alterations, substantiating that juxtacortical and peripheral chondrosarcomas are two clinicopathologically different entities with a different genetic background. Central chondrosarcomas were previously found to be peridiploid with limited LOH, most frequent at 9p21. In the current study, chromosome 9 was involved in five of seven central chondrosarcomas compared with only one of four peripheral chondrosarcomas. Three central tumors showed involvement of the 9pl2-22 region, suggesting an important role for chromosome 9 in the oncogenesis of central chondrosarcoma. Moreover, trisomy 22 was found in four central chondrosarcomas only.


Subject(s)
Bone Neoplasms/genetics , Chondrosarcoma/genetics , Chromosomes, Human, Pair 22/genetics , Chromosomes, Human, Pair 9/genetics , Trisomy , Adolescent , Adult , Aged , Aged, 80 and over , Bone Neoplasms/classification , Bone Neoplasms/pathology , Chondrosarcoma/classification , Chondrosarcoma/pathology , Cytogenetic Analysis , DNA, Neoplasm/analysis , Female , Flow Cytometry , Humans , Male , Middle Aged
5.
Hum Immunol ; 61(6): 565-74, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10825585

ABSTRACT

To increase the immunogenicity of leukemic cells, attempts were made to generate dendritic-like antigen presenting cells (DC) from AML blasts from 14 patients with AML FAB classifications M0-M5. Leukemic cells were cultured in the presence or absence of various cytokines including GM-CSF, SCF, TNF-alpha, IL-4, and gamma-interferon. After various intervals recovery of viable cells was measured and expression of CD80, CD86, CD40, CD54, CD58, and CD11a was analyzed by flow cytometry. Functionally, DC derived from six AML samples were tested in a mixed lymphocyte response (MLR) using HLA-DR mismatched donor T cells as responder cells. Proliferation (5/14) or increased survival (7/14) of AML cells was observed in the presence of GM-CSF, SCF, and TNF-alpha. Only in the AML M2, M3, and M4 FAB subtypes proliferation was found. GM-CSF, SCF, and TNF-alpha induced morphologic changes typical for DC and increased the expression of costimulatory and adhesion molecules. No significant effect of IL-4 or gamma-interferon was observed. The day of maximal expression of these molecules varied. In cases with minor upregulation of CD80 or CD86, no further stimulation using CD40-L activation was observed. In the three cases tested, the DC-like cells retained the chromosomal abnormalities present in the original AML cells. In five out of six cases tested an increase in allostimulatory capacity was found at the day of maximal expression of costimulatory and adhesion molecules. In two patients a decrease in stimulatory capacity was found at day 7 compared with day 2 correlating with a decreased expression of these molecules. In conclusion, AML cells can be induced to increase their stimulatory capacity by upregulating costimulatory and adhesion molecules.


Subject(s)
Dendritic Cells/immunology , Leukemia, Myeloid/immunology , Acute Disease , Adult , Aged , Antigens, CD/analysis , B7-1 Antigen/analysis , B7-2 Antigen , CD40 Antigens/analysis , CD40 Antigens/pharmacology , Cell Count , Coculture Techniques , Cytogenetic Analysis , Cytokines/pharmacology , Dendritic Cells/drug effects , Female , Flow Cytometry , Humans , Immunization , Male , Membrane Glycoproteins/analysis , Middle Aged , Tumor Cells, Cultured
6.
Genes Chromosomes Cancer ; 28(1): 14-22, 2000 May.
Article in English | MEDLINE | ID: mdl-10738298

ABSTRACT

Reciprocal translocations involving the MLL gene on chromosome band 11q23 have been observed in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In AML, identification of MLL breakpoints is an important prognostic factor. Breakpoints are clustered in an 8 kb DNA fragment (bcr) and can be detected by Southern blotting or fluorescence in situ hybridization (FISH) analysis. Our objective in this study was to design a DNA probe set that enables optimal detection of MLL rearrangements using interphase FISH. Two PAC clones, 217A21 and 167K13, spanning the MLL gene with a minimal overlap in the bcr were isolated and labeled. Twenty-seven AML/ALL patients with cytogenetic 11q23 abnormalities, seven AML/ALL patients without 11q23 abnormalities but MLL rearrangement by Southern blotting, and eight healthy donors were analyzed by FISH. We compared this double-color FISH analysis with FISH using a YAC clone (yB22B2) and with Southern blotting. The PAC probe combination detects an MLL breakpoint in all cases with MLL rearrangement detected by Southern blotting except for cases with a partial tandem duplication detected by reverse transcriptase-polymerase chain reaction (RT-PCR). FISH using the PAC probes also detected MLL breakpoints in four cases with MLL deletions telomeric to the breakpoint that could not be detected by the single probe yB22B2. This new probe set provides a reliable and rapid assay for the diagnosis of AML and ALL patients with MLL/11q23 breakpoints.


Subject(s)
Chromosome Breakage/genetics , Chromosomes, Human, Pair 11/genetics , DNA Probes/genetics , DNA-Binding Proteins/genetics , In Situ Hybridization, Fluorescence/methods , Interphase/genetics , Leukemia/genetics , Proto-Oncogenes , Transcription Factors , Acute Disease , Adolescent , Adult , Aged , Bacteriophage P1/genetics , Child, Preschool , Cloning, Molecular , Contig Mapping , Female , Histone-Lysine N-Methyltransferase , Humans , Karyotyping , Male , Middle Aged , Myeloid-Lymphoid Leukemia Protein , Translocation, Genetic/genetics
7.
Cancer Genet Cytogenet ; 112(2): 178-80, 1999 Jul 15.
Article in English | MEDLINE | ID: mdl-10686949

ABSTRACT

We report here the cytogenetic analysis of a follicular adenoma of the thyroid which revealed an abnormal clone with a t(X;10)(p22;q24) and a t(1;10)(q21;q11) together with normal cells. Fluorescence in situ hybridization (FISH) with YACs 273E3 and 344H4, which are located on 10q11.2 and are specific for the RET protooncogene, showed no abnormalities. It would therefore appear that this gene is not involved in the particular tumor, as has been reported in a number of papillary thyroid carcinomas. Several chromosomal aberrations have been suggested as been specific for follicular thyroid adenoma. However, until now, only a few such cases have been reported which involve structural abnormalities of chromosomes 10q11.2 and 10q24. We believe this to be the first report of a follicular thyroid adenoma with a t(X;10)and a t(1;10).


Subject(s)
Adenoma/genetics , Drosophila Proteins , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Translocation, Genetic , Adult , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 10 , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Proto-Oncogene Proteins c-ret , X Chromosome
8.
Cancer Genet Cytogenet ; 105(2): 109-12, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9723025

ABSTRACT

Chromosome analysis of a chondroblastoma of the right distal femur in a 31-year-old male patient revealed a ring chromosome 4 in approximately one-third of the analyzed cells. The remaining cells had a normal karyotype. These findings were subsequently confirmed by fluorescence in situ hybridization (FISH) with a chromosome-4-specific library. FISH with cosmids pC847.351 (4p16.3) and cT171 (4q35) revealed that fewer than 300 kilobase pairs (kbp) are deleted. To our knowledge, ring chromosome 4 has never been reported in this type of neoplasm. There are, however, several reports of chondroblastoma with other chromosome abnormalities, but the relation of these anomalies to this tumor specifically is unclear. In this report, we also provide a review of the literature concerning cytogenetic studies in chondroblastoma. The possible significance of ring chromosome 4 in this type of tumor is discussed.


Subject(s)
Chondroblastoma/genetics , Ring Chromosomes , Adult , Chondroblastoma/pathology , Chondroblastoma/therapy , Female , Humans , Male
9.
Prenat Diagn ; 17(2): 173-9, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9061768

ABSTRACT

We present here a case report of a fetus with a kidney anomaly and dilated occipital horns, detected initially by echoscopy at 29 weeks' amenorrhoea. After 31 weeks of gestation, the proband was born with clinical symptoms of Miller-Dieker syndrome. This was subsequently confirmed by fluorescence in situ hybridization (FISH), but not by conventional cytogenetic analysis. FISH using a cocktail of cosmids (c197-2, c197-4, c197-9) from the Miller-Dieker critical region showed a deletion of 17p13.3 in one homologue of chromosome 17. Additional FISH studies revealed a subtle 17p;20q translocation in the father, his sister, and the paternal grandmother. Hence, our patient is a carrier of an unbalanced 17;20 translocation resulting in a partial deletion of 17p and a partial trisomy 20q. Whenever kidney anomalies and dilated occipital horns are observed together with polyhydramnios during prenatal ultrasound examination, the possibility of Miller-Dieker syndrome should be suspected. In such cases, prenatal and/or postnatal chromosome studies should also include FISH analysis with the appropriate probes.


Subject(s)
Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 20 , Translocation, Genetic , Ultrasonography, Prenatal , Brain/abnormalities , Female , Gene Deletion , Gestational Age , Humans , In Situ Hybridization, Fluorescence , Infant, Newborn , Kidney/abnormalities , Kidney/diagnostic imaging , Male , Occipital Lobe/abnormalities , Occipital Lobe/diagnostic imaging , Pedigree , Pregnancy , Syndrome , Trisomy
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