Alterations of the short arm of chromosome 9p in lymphoid malignancies
Author: Heyman, Mats
Date: 1996-06-13
Location: Radiumhemmets föreläsningssal, Karolinska sjukhuset
Time: 9.15
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
Abstract
Malignant disease evolves through the successive accumulation of genetic lesions affecting growth-controlling genes in the cell-clone undergoing malignant transformation. 9p21 has long been suspected to harbour a tumour suppressor gene, because of frequent deletions of this region in malignancies including acute lymphocytic leukaemia (ALL). The Type I interferon (IFN) genes map to this region and IFNs exert antiproliferative effects in vitro and antitumour effects in vivo. These facts lead to the hypothesis that the IFN-genes act as tumour suppressor genes in ALL.
We thus studied the IFN-genes in ALL-cells and included functional aspects of the IFN-system, since clinical unresponsiveness to IFN sometimes results from lack of susceptibility to IFN. IFN-gene deletions and other defects of the IFN-system occurred in approximately 50% of primary ALL-cells and more frequently in malignant T-cell lines. However, loss of IFN-genes did not correlate to susceptibility of the cells to IFN. Nor did loss of one allele of the IFN-gene locus abrogate the IFN-producing capacity. Simultaneously, other investigations indicated that the minimal region of overlap for the 9p-deletions mapped outside the IFN-gene cluster. In conclusion; a role for the Type I IFN-genes as tumour suppressor genes in ALL is unlikely, but some ALL-clones may have inactivated other parts of the IFN-system during the malignant transformation.
In 1994 the cell-cycle regulating genes p15INK4B and p16INK4 were mapped to the mimimally deleted region. The integrity of the p15INK4B and p16INK4 genes were therefore studied in DNA from altogether 79 ALL-patients by means of Southern blotting, single strand conformational polymorphism analysis (SSCP) and nucleotide sequencing. Loss of heterozygosity (LOH) for9p21 was investigated by microsatellite analysis. Inactivating homozygous deletions were found inone or both genes in 28% of the clones and in a further 18% hemizygous deletions or LOH were detected. Exclusive homozygous deletion was more common in the p16INK4 gene and two of the hemizyguosly deleted clones carried inactivating intragenic mutations in the p16INK4 gene. Three patients initially thought to carry exclusive homozygous deletions of the pl5INK4B gene, were found to have complete deletions of the alternative Elb-exon of the p16INK4 gene. These results indicate that the p16INK4 gene acts as a tumour suppressor gene in ALL. A similar role for the pl5INK4B gene is conceivable considering results from these and other studies but has so far not been proven.
The prognostic importance of pl5INK4B / p16INK4 gene-inactivation and other 9p alterations was assessed by statistical correlation of the genetic data with treatment outcome. Gene inactivation was found to be an adverse prognostic marker and an independent predictor of relapse, second in strength only to white blood cell count. Patients with loss of one allele of the 9p21 region did not differ from non-deleted cases with regard to prognosis. A patient with a T-cell lymphoblastic lymphoma refractory to initial chemotherapy, but responding briefly to a-IFN therapy, was studied in detail. Genetically different subclones were found at presentation and after progression of the disease. The common origin of the subclones was verified and clonal selection was thus the mechanism for the in vivo IFN-resistance. Both clones had lost both alleles of the pl5INK4B and p16lNK4 genes, but the homozygous deletions had occurred through distinct genetic mechanisms.
We thus studied the IFN-genes in ALL-cells and included functional aspects of the IFN-system, since clinical unresponsiveness to IFN sometimes results from lack of susceptibility to IFN. IFN-gene deletions and other defects of the IFN-system occurred in approximately 50% of primary ALL-cells and more frequently in malignant T-cell lines. However, loss of IFN-genes did not correlate to susceptibility of the cells to IFN. Nor did loss of one allele of the IFN-gene locus abrogate the IFN-producing capacity. Simultaneously, other investigations indicated that the minimal region of overlap for the 9p-deletions mapped outside the IFN-gene cluster. In conclusion; a role for the Type I IFN-genes as tumour suppressor genes in ALL is unlikely, but some ALL-clones may have inactivated other parts of the IFN-system during the malignant transformation.
In 1994 the cell-cycle regulating genes p15INK4B and p16INK4 were mapped to the mimimally deleted region. The integrity of the p15INK4B and p16INK4 genes were therefore studied in DNA from altogether 79 ALL-patients by means of Southern blotting, single strand conformational polymorphism analysis (SSCP) and nucleotide sequencing. Loss of heterozygosity (LOH) for9p21 was investigated by microsatellite analysis. Inactivating homozygous deletions were found inone or both genes in 28% of the clones and in a further 18% hemizygous deletions or LOH were detected. Exclusive homozygous deletion was more common in the p16INK4 gene and two of the hemizyguosly deleted clones carried inactivating intragenic mutations in the p16INK4 gene. Three patients initially thought to carry exclusive homozygous deletions of the pl5INK4B gene, were found to have complete deletions of the alternative Elb-exon of the p16INK4 gene. These results indicate that the p16INK4 gene acts as a tumour suppressor gene in ALL. A similar role for the pl5INK4B gene is conceivable considering results from these and other studies but has so far not been proven.
The prognostic importance of pl5INK4B / p16INK4 gene-inactivation and other 9p alterations was assessed by statistical correlation of the genetic data with treatment outcome. Gene inactivation was found to be an adverse prognostic marker and an independent predictor of relapse, second in strength only to white blood cell count. Patients with loss of one allele of the 9p21 region did not differ from non-deleted cases with regard to prognosis. A patient with a T-cell lymphoblastic lymphoma refractory to initial chemotherapy, but responding briefly to a-IFN therapy, was studied in detail. Genetically different subclones were found at presentation and after progression of the disease. The common origin of the subclones was verified and clonal selection was thus the mechanism for the in vivo IFN-resistance. Both clones had lost both alleles of the pl5INK4B and p16lNK4 genes, but the homozygous deletions had occurred through distinct genetic mechanisms.
Issue date: 1996-05-23
Publication year: 1996
ISBN: 91-628-2085-0
Statistics
Total Visits
Views | |
---|---|
Alterations ...(legacy) | 230 |
Alterations ... | 139 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Alterations ... | 1 | 0 | 2 | 3 | 0 | 0 | 0 |
Top country views
Views | |
---|---|
United States | 86 |
Sweden | 53 |
Germany | 52 |
China | 44 |
South Korea | 14 |
Ireland | 10 |
Finland | 6 |
Greece | 6 |
France | 5 |
Netherlands | 5 |
Top cities views
Views | |
---|---|
Kiez | 18 |
Seoul | 14 |
Dublin | 10 |
Sunnyvale | 10 |
Ashburn | 9 |
University Park | 7 |
Shenzhen | 6 |
Athens | 5 |
Stockholm | 5 |
Woodbridge | 5 |