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Karyotypic abnormalities and prognosis in adult chronic granulocytic leukemia, acute myeloid leukemia and acute lymphoblastic leukemia
ABSTRACTS OF THE 7th ANNUAL MEETING This paper presents the results of chromosome studies performed in our unit on a consecutive series of patients, at diagnosis of ALL, between January 1981 and December 1982. Overnight marrow cultures were carried out on 94 patients; 60 were found to have abnormal karyotypes and 34 had no detectable abnormality. Trypsin G-banding was successful in 75 patients. The most commonly observed abnormality was numerical, i.e. hyperdiploidy of >50 chromosomes/cell, which correlated with a good prognosis. Specific structural abnormalities i.e. t(4;l I), t(8;14) and t(9;22) were found t o be associated with the poorest prognosis. A new specific translocation between chromosomes 1 and 19 was identified in 6 patients, but its relationship to prognosis is as yet unclear. These results are part of a 3 yr project on ALL, in conjunction with the Royal Children’s Hospital and the Cancer Institute who are supplying the clinical and immunologic data for correlation with the cytogenetics findings.
EFFECT OF FRAGILE SITES ON RECOMBINATION J . c . M U L L E Y ,J’ U D I T HH A Y , >L. J . SHEFFIELD’ A N D G . R. SUTHERLAND’ ’Department of Histopathology, ’Medical Genetics and Epidemiology Unit, The Adelaide Children’s Hospital. >AustralianRed Cross Society, Blood Transfusion Service, Adelaide A large kindred with a fragile site at band 6p23 has now been completely studied for recombination between the fragile site and HLA. Recombination was observed in four of the 20 offspring in whom it could occur. The length of chromosome between these markers is 20 centimorgans, giving a likely regional localization for HLA between the midpoint of 6p22 and a previously known proximal limit at 6 ~ 2 1 . 2 . This agrees closely with other recent evidence. The genetic length of chromosome between fragile sites at 1Oq23 and IOq25 is also consistent with estimares using different methods. There is no apparent effect of fragile sites on recombination.
A SEARCH FOR LINKAGE IN A KINDRED WITH EPIDERMOLYSIS BULLOSA J . c. MULLEY,’ c. NiCHOLLS,’ T. TURNER’ AND G . R. SUTHERLAND’ ‘Department of”Histopathology, >Senior Visiting Dermatologist, The Adelaide Children’s Hospital Epidermolysis bullosa is a genetically and clinically heterogeneous disorder of the skin. There are several forms with an autosomal dominant mode of transmission which are usually fully penetrant. Variable expression can make classification difficult in some cases, as demonstrated in the family presented. Mapping epidermolysis bullosa loci to different chromosomal regions would provide the genetical criteria for classification. The locus for one form of epidermolysis bullosa is known to be linked to the structural locus for glutamic pyruvic transaminase. Variation between families having common epidermolysis bullosa loci could be attributable to different alleles at the same locus. Linkage analysis (by LIPED-version 3) is presented for another large kindred. There is a suggestion of linkage with the Duffy blood group that requires further investigation. The genornic localization of all epidermolysis bullosa loci could provide a basis for precise clinical diagnosis by linkage in new families presenting with symptoms.
CHROMOSOME BREAKAGE IN NORMAL MURINE MACROPHAGES A. R. MURCHA N D J . M. PAPADIMITRIOU Department of Pathology, University of Western Australia, Queen Elizabeth II Medical Centre, Perth Macrophages are large phagocytic cells found in most tissues of the body. They are derived from the circulating monocyte population and play a primary role in host defence mechanisms. Cytogenetic
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investigation of several populations of murine macrophages has been carried out. Gaps, breaks and other re-arrangements have been found in up to 50% of the metaphases examined in 7 d cultures of exudate peritoneal macrophages and in from 14-36’70 of metaphases in direct, in vivo preparations of resident peritoneal macrophages. In vivo preparations of both resident alveolar macrophages and exudate peritoneal macrophages have shown a much lower rate of chromosomal damage (0-8’70). Bone-marrow metaphases, prepared as controls from the same animals as were used to collect macrophages, showed damage in only 0-2’70 of metaphases. Macrophages are the only known cell type to display such damage in normal healthy mammals. The most likely reason for this high rate of damage is that macrophages produce an abundance of oxygen derived free-radicals (which are known to produce chromosomal damage) during the oxidative burst associated with phagocytosis. To test this hypothesis, macrophage cultures were treated with several free-radical scavengers, which had been found t o be effective in reducing chromosome damage in other systems. Acetyl-cysteine and glutathione were found to produce a significant reduction in chromosomal damage, when compared with control cultures, but the enzymes superoxide dismutase and catalase had no effect. The reasons for this are not clear, but may be associated with their poor ability to penetrate cell membranes.
KARYOTYPIC ABNORMALITIES AND PROGNOSIS IN ADULT CHRONIC GRANULOCYTIC LEUKEMIA, ACUTE MYELOID LEUKEMIA AND ACUTE LYMPHOBLASTIC LEUKEMIA C . J . PARKER, R. P . H E R R M A N NL. , CHIPPERA N D B. F. MEYER Cytogenetics Laboratory, Haematology Department, Royal Perth Hospital Adult patients with chronic granulocytic leukemia (CGL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) studied over the 5 yr period 1977-1981 were examined. The patients in each category were divided into those with normal marrow chromosomal profiles at presentation and those with chromosomal abnormalities of a clonal nature. The survival rates for the 2 groups were compared. CGL patients were regarded as “standard” if a single Philadelphia chromosome was the only abnormality and “non-standard” if there were additional chromosomal abnormalities. Twenty-eight patients with CGL, 45 patients with AML and 21 patients with ALL were assessed. Of these, 14 of the CGL, 22 of the AML and 15 of the ALL patients were excluded because either chromosomal analysis was unsuccessful on marrow, analysis was not performed before treatment or there were insufficient clinical data. The remaining groups were too small for statistical analysis; however median survival rates suggested that there was no difference between the normal and abnormal groups with AML but that there was longer survival in those with “standard” CGL at presentation. Only 1 patient with adult ALL had a normal chromosome profile at presentation and his survival was less than the median survival of the 5 patients with abnormal chromosomes.
FACTORS AFFECTING THE INTERPRETATION OF GENETIC RISKS IN THE SPINAL MUSCULAR ATROPHIES JOHN PEARNDepartment of Child Health, Royal Children’s Hospital, Brisbane The spinal muscular atrophies (SMA) are genetically heterogeneous; infantile, childhood and adult-onset forms occur, and both dominant and recessive genes may cause the fundamental motor neurone abiotrophy which causes the clinical picture. This paper reports the result of a study to determine life expectancy in this group of conditions. One hundred and forty cases of the chronic childhood form of the
EFFECT OF FRAGILE SITES ON RECOMBINATION J . c . M U L L E Y ,J’ U D I T HH A Y , >L. J . SHEFFIELD’ A N D G . R. SUTHERLAND’ ’Department of Histopathology, ’Medical Genetics and Epidemiology Unit, The Adelaide Children’s Hospital. >AustralianRed Cross Society, Blood Transfusion Service, Adelaide A large kindred with a fragile site at band 6p23 has now been completely studied for recombination between the fragile site and HLA. Recombination was observed in four of the 20 offspring in whom it could occur. The length of chromosome between these markers is 20 centimorgans, giving a likely regional localization for HLA between the midpoint of 6p22 and a previously known proximal limit at 6 ~ 2 1 . 2 . This agrees closely with other recent evidence. The genetic length of chromosome between fragile sites at 1Oq23 and IOq25 is also consistent with estimares using different methods. There is no apparent effect of fragile sites on recombination.
A SEARCH FOR LINKAGE IN A KINDRED WITH EPIDERMOLYSIS BULLOSA J . c. MULLEY,’ c. NiCHOLLS,’ T. TURNER’ AND G . R. SUTHERLAND’ ‘Department of”Histopathology, >Senior Visiting Dermatologist, The Adelaide Children’s Hospital Epidermolysis bullosa is a genetically and clinically heterogeneous disorder of the skin. There are several forms with an autosomal dominant mode of transmission which are usually fully penetrant. Variable expression can make classification difficult in some cases, as demonstrated in the family presented. Mapping epidermolysis bullosa loci to different chromosomal regions would provide the genetical criteria for classification. The locus for one form of epidermolysis bullosa is known to be linked to the structural locus for glutamic pyruvic transaminase. Variation between families having common epidermolysis bullosa loci could be attributable to different alleles at the same locus. Linkage analysis (by LIPED-version 3) is presented for another large kindred. There is a suggestion of linkage with the Duffy blood group that requires further investigation. The genornic localization of all epidermolysis bullosa loci could provide a basis for precise clinical diagnosis by linkage in new families presenting with symptoms.
CHROMOSOME BREAKAGE IN NORMAL MURINE MACROPHAGES A. R. MURCHA N D J . M. PAPADIMITRIOU Department of Pathology, University of Western Australia, Queen Elizabeth II Medical Centre, Perth Macrophages are large phagocytic cells found in most tissues of the body. They are derived from the circulating monocyte population and play a primary role in host defence mechanisms. Cytogenetic
105
investigation of several populations of murine macrophages has been carried out. Gaps, breaks and other re-arrangements have been found in up to 50% of the metaphases examined in 7 d cultures of exudate peritoneal macrophages and in from 14-36’70 of metaphases in direct, in vivo preparations of resident peritoneal macrophages. In vivo preparations of both resident alveolar macrophages and exudate peritoneal macrophages have shown a much lower rate of chromosomal damage (0-8’70). Bone-marrow metaphases, prepared as controls from the same animals as were used to collect macrophages, showed damage in only 0-2’70 of metaphases. Macrophages are the only known cell type to display such damage in normal healthy mammals. The most likely reason for this high rate of damage is that macrophages produce an abundance of oxygen derived free-radicals (which are known to produce chromosomal damage) during the oxidative burst associated with phagocytosis. To test this hypothesis, macrophage cultures were treated with several free-radical scavengers, which had been found t o be effective in reducing chromosome damage in other systems. Acetyl-cysteine and glutathione were found to produce a significant reduction in chromosomal damage, when compared with control cultures, but the enzymes superoxide dismutase and catalase had no effect. The reasons for this are not clear, but may be associated with their poor ability to penetrate cell membranes.
KARYOTYPIC ABNORMALITIES AND PROGNOSIS IN ADULT CHRONIC GRANULOCYTIC LEUKEMIA, ACUTE MYELOID LEUKEMIA AND ACUTE LYMPHOBLASTIC LEUKEMIA C . J . PARKER, R. P . H E R R M A N NL. , CHIPPERA N D B. F. MEYER Cytogenetics Laboratory, Haematology Department, Royal Perth Hospital Adult patients with chronic granulocytic leukemia (CGL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) studied over the 5 yr period 1977-1981 were examined. The patients in each category were divided into those with normal marrow chromosomal profiles at presentation and those with chromosomal abnormalities of a clonal nature. The survival rates for the 2 groups were compared. CGL patients were regarded as “standard” if a single Philadelphia chromosome was the only abnormality and “non-standard” if there were additional chromosomal abnormalities. Twenty-eight patients with CGL, 45 patients with AML and 21 patients with ALL were assessed. Of these, 14 of the CGL, 22 of the AML and 15 of the ALL patients were excluded because either chromosomal analysis was unsuccessful on marrow, analysis was not performed before treatment or there were insufficient clinical data. The remaining groups were too small for statistical analysis; however median survival rates suggested that there was no difference between the normal and abnormal groups with AML but that there was longer survival in those with “standard” CGL at presentation. Only 1 patient with adult ALL had a normal chromosome profile at presentation and his survival was less than the median survival of the 5 patients with abnormal chromosomes.
FACTORS AFFECTING THE INTERPRETATION OF GENETIC RISKS IN THE SPINAL MUSCULAR ATROPHIES JOHN PEARNDepartment of Child Health, Royal Children’s Hospital, Brisbane The spinal muscular atrophies (SMA) are genetically heterogeneous; infantile, childhood and adult-onset forms occur, and both dominant and recessive genes may cause the fundamental motor neurone abiotrophy which causes the clinical picture. This paper reports the result of a study to determine life expectancy in this group of conditions. One hundred and forty cases of the chronic childhood form of the