The pathophysiology and clinical severity of -thalassemia are related to the degree of ␣/non-␣-chain imbalance. A triplicated ␣-globin gene locus can exacerbate effects of excess ␣-chains caused by a defective -globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the ␣␣␣ anti-3.7 allele and a mutation in the -globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same -thalassemia mutation: in one family, two individuals had the same ␣-and -globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated ␣-globin gene, 
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+27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A 2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical ␣-and -globin genotypes. Interaction with a triplicated ␣-gene can play a role in the clinical presentation of patients with defective -globin gene expression and should be considered in the diagnosis of atypical cases.
The T-lymphoma cell line Hut78 contains a rearranged c-myc oncogene derived from a translocation between the long arms of chromosomes 8 and 2; the event deletes the 3' end of the gene, causing the loss of the transcribed AT-rich sequence. It has recently been shown that the mutant c-myc mRNA is several-fold more stable than normal c-myc mRNA. We have assessed the tumorigenicity of the mutant c-myc allele by transfecting this gene and its normal counterpart into NIH3T3 cells, together with a neomycin resistance gene. Following selection for G-418 resistance, the cells were injected into nude mice. Tumors containing integrated c-myc arose in animals injected with cells transfected by the mutated, but not by the normal, allele. The results suggest that this rearranged c-myc bears a tumorigenic activity not observed in other naturally occurring mutated c-myc alleles and may have directly contributed to the tumorigenic event in the Hut78 cell line.
Parts of the Bcr/Abl hybrid transcript supposed to be important for its transforming ability were sequenced in a series of CML blast crises, in order to evaluate the possible presence of alterations responsible for the disease transition from the chronic to the acute phase. In addition, the N- and Ki-ras as well as the p53 involvement was investigated by exploring their structure and expression in the same patients. We used traditional types of molecular analysis including Southern and Northern blot, together with methods that allow a rapid detection of point mutations and microdeletions, such as SSCP, single strand conformation polymorphism and direct sequencing. The results obtained may be summarized as follows: no alterations were found in the parts of the Bcr/Abl transcripts investigated in the present study (SH2, SH3 and the region surrounding codon 832); p53 alterations were observed in 5% and N- and Ki-RAS mutations in 5% of the cases examined. These molecular defects are therefore responsible for the clinical progression of the Ph1-positive CML only in a minority of cases.
We amplified and sequenced the rearranged immunoglobulin heavy chain VDJ genomic unit in B-leukemias and used it as a clone-specific marker for the molecular monitoring of the patients during and after therapeutic treatment. The method described is patient-specific rather than disorder-specific, more sensitive and less time-consuming than other conventional techniques for the detection of minimal residual disease. We propose reproducible and quick procedures, from DNA extraction to Southern blotting, that can be easily performed in any clinical laboratory and also applied to other kinds of investigation.
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