Alterations of the short arm of chromosome 9p in lymphoid malignancies
Sammanfattning: CHROMOSOME 9p ALTERATIONS IN LYMPHOID MALIGNANCIES by Mats Heyman Department of Oncology-Pathology, Radiumhemmet, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden.Malignant disease evolves through the successive accumulation of genetic lesions affecting growth-controlling genes in the cell-clone undergoing malignant transformation. 9p21 has long beensuspected to harbour a tumour suppressor gene, because of frequent deletions of this region inmalignancies including acute lymphocytic leukaemia (ALL). The Type I interferon (IFN) genesmap 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. Wethus studied the IFN-genes in ALL-cells and included functional aspects of the IFN-system, sinceclinical unresponsiveness to IFN sometimes results from lack of susceptibility to IFN. IFN-genedeletions and other defects of the IFN-system ocurred in approximately 50% of primary ALL-cellsand more frequently in malignant T-cell lines. However, loss of IFN-genes did not correlate tosusceptibility 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 ofoverlap for the 9p-deletions mapped outside the IFN-gene cluster. In conclusion; a role for theType I IFN-genes as tumour suppressor genes in ALL is unlikely, but some ALL-clones may haveinactivated other parts of the IFN-system during the malignant transformation.In 1994 the cell-cycle regulating genes p15INK4B and p16INK4 were mapped to the mimimallydeleted region. The integrity of the p15INK4B and p16INK4 genes were therefore studied in DNAfrom altogether 79 ALL-patients by means of Southern blotting, single strand conformationalpolymorphism analysis (SSCP) and nucleotide sequenceing. 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 weredetected. Exclusive homozygous deletion was more common in the p16INK4 gene and two of thehemizyguosly deleted clones carried inactivating intragenic mutations in the p16INK4 gene. Threepatients initially thought to carry exclusive homozygous deletions of the pl5INK4B gene, werefound to have complete deletions of the alternative Elb-exon of the p16INK4 gene. These resultsindicate that the p16INK4 gene acts as a tumour suppressor gene in ALL. A similar role for thepl5INK4B gene is conceivable considering results from these and other studies but has so far notbeen proven. The prognostic importance of pl5INK4B / p16INK4 gene-inactivation and other 9palterations was assessed by statistical correlation of the genetic data with treatment outcome. Geneinactivation 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 regiondid not differ from non-deleted cases with regard to prognosis.A patient with a T-cell lymphoblastic lymphoma refractory to initial chemotherapy, but respondingbriefly to a-IFN therapy, was studied in detail. Genetically different subclones were found atpresentation and after progression of the disease. The common origin of the subclones was verifiedand clonal selection was thus the mechanism for the in vivo IFN-resistance. Both clones had lostboth alleles of the pl5INK4B and p16lNK4 genes, but the homozygous deletions had occured throughdistinct genetic mechanisms.~) Mats HeymanISBN: 91-628-2085-0
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