The analysis of molecular lesions in B-DLCL may be useful for a better diagnostic definition; however, in this study we were unable to show that the evaluated genetic lesions had a significant impact on clinical outcome.

In order to verify the genetic factors influencing the clinical expression of beta-thalassemia we have studied 292 Italian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The beta-globin gene mutations were defined in all cases. The number of alpha-globin genes and the integrity of specific control regions of the beta-globin cluster--gamma promoters and beta-Locus Control Region (beta-LCR)--were studied in selected cases. Homozygosity for mild mutations (group I) accounts for 24% of the intermedia patients and it is not represented among major patients. Forty-four percent of intermedia patients had combinations of mild/severe (group II) mutations and 32% had homozygosity or double heterozygosity for severe mutations (group III). Seventy-six percent of patients with thalassemia major were classified in group III and 24% in group II. Deletion type-alpha3.7 thalassemia, assessed in a part of the cases, was found in 5% of thalassemia major and 19.5% of intermedia patients in groups II and III. Structural analysis of gamma promoters and beta-LCR HS2 and HS4 regions, carried out in order to look for alterations associated with Hb F increase, did not reveal new mutations. Only rare polymorphic changes were observed at the HS2 and HS4 level. The -158G gamma C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 beta-thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated alpha-locus. We have been unable to find a molecular basis for the benign clinical course in approximately 20% of patients with thalassemia intermedia. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition.

A new type of hemoglobin F, in which isoleucine in position 75 (E 19) of the gamma chain is replaced by a threonine residue, has been found in 29 out of 32 homozygotes for beta thalassemia. The amount of this hemoglobin ranges from traces to 40% of the total Hb F. The same gamma75 Thr chain is also present in the Hb F of 40% of normal newborns and premature infants examined, of one 14-week-old fetus and in one out of 3 patients with aplastic anemia and raised levels of Hb F. Our results strongly suggest that the synthesis of this new chain is under the control of a gamma gene nonallelic with those coding for Agamma and Ggamma chains.

A family was studied in which two inherited defects of the non‐alpha‐globin cluster segregate: Greek hereditary persistence of fetal hemoglobin (HPFH) and beta‐thalassemia. Fragments of the non‐alpha‐globin cluster from two patients were cloned in cosmid and phage lambda vectors, and assigned to either the HPFH or beta‐thalassemic chromosome on the basis of the demonstration of a polymorphic BglII site in the HPFH gamma‐globin cluster. The thalassemic beta‐globin gene carries a mutation at nucleotide 1 of the intervening sequence I, known to cause beta zero‐thalassemia; the beta‐globin gene from the HPFH chromosome is entirely normal, both in the intron‐exon sequence and in 5′ flanking regions required for transcription. As the compound HPFH/beta‐thalassemia heterozygote synthesizes HbA, these data prove that the HPFH beta‐globin gene is functional, although at a decreased rate; its lower activity is likely to be due to a distant mutation. The HPFH A gamma‐globin gene shows only two mutations: a T–‐C substitution in the large intervening sequence (responsible for the BglII polymorphic site) and a C–‐T substitution 196 nucleotides 5′ to the cap site; the 5′ flanking sequence is normal up to ‐1350 nucleotides upstream from the gene. Circumstantial evidence suggests that the mutation at ‐196 may be responsible for the abnormally high expression of the A gamma‐globin gene.

A new and rare type of Bcr/Abl junction between exon C3 of the 3′ portion of the Bcr gene and Abl exon 2 has been identified in the leukemic cells of two Ph1-positive chronic myelogenous leukemia patients in chronic phase. This is the fourth type of Bcr/Abl junction so far identified in Ph1-positive hematologic malignancies and is a consequence of an unusual breakpoint position on chromosome 22 that falls approximately 20 kb downstream of the major breakpoint cluster region (bcr) of the Bcr gene. The new hybrid mRNA is 540 base pairs (bp) longer than that expressed by the K562 cell line and could codify for a Bcr/Abl protein carrying 180 additional aminoacids with respect to the larger P210 protein so far identified. The hematologic phenotype expressed by the two patients carrying this unusual type of Bcr/Abl rearrangement does not significantly differ from that commonly seen in chronic myelogenous leukemia.