A somatic mutation(s), acquired during the evolution of preleukemia in a 75-year-old Caucasian male of North European origin, resulted in a marked decrease in a-globin mRNA. The small amount of at-globin mRNA present in bone marrow cells was normally processed, had a normal (a1/at2)-globin mRNA ratio, and was translated normally. No detectable N-globin mRNA was found. The a-and C-globin genes were both hypomethylated and restriction endonuclease maps of the a-and {-globin genes were comparable in the patient's marrow and fibroblast DNA. The data are most consistent with the acquisition of a mutation(s) that resulted in decreased expressioniof all four a-globin genes.A B Acquired a-thalassemia (Hb H disease) has been reported in at least 19 patients with a variety of hematological disorders, including erythroleukemia (1-3), sideroblastic anemia (4-6), myelofibrosis (7,8), chronic myelogenous leukemia (9), acute leukemia (10-12), other less-defined myeloproliferative syndromes (13,14), and most recently chronic lymphocytic leukemia (15). Since these leukemias are clonal disorders, the mutation that results in loss of a-globin gene expression may be related to that which leads to the abnormal growth properties of leukemia cells. Previous studies of acquired Hb H disease in leukemias have documented a profound reduction of the (a/ A)-globin biosynthetic ratios in all patients (5,7,12,13). Analysis of total bone marrow RNA from two patients has shown (a/ 8)-globin mRNA ratios of 0.01 (12) and 0.05 (5). DNA-cDNA solution hybridization analysis revealed no reduction in a-globin gene sequence concentration in the DNA of one patient (12). In this report, we describe a study of a 75-year-old Caucasian male in whom marked reduction of transcription of all four a-globin genes arose as part of a preleukemic syndrome.MATERIALS AND METHODS Purification and electrophoresis of poly(A)+ mRNA was as described (16-18). For S1 nuclease mapping, the a-globin probe was synthesized on a single-stranded DNA template prepared from an M13 mp7 a-globin gene recombinant (19), and the Tglobin probe was prepared by nick-translation (20) of a DNA fragment that included the 5' end of {1 gene. After hybridization and S1 nuclease treatment, the products were separated on 8% polyacrylamide denaturing gels. Relative amounts of a,-and a2-globin mRNA were determined by extension of a 5'-end 3P-labeled 31-base-pair-a-globin cDNA primer with avian myeloblastosis virus reverse transcriptase as described (21).Single and double digestions of high molecular weight DNA (20-40 pug per lane) were carried out as described (22, (Hb, 8.9 g/dl) with a reticulocyte count of 9%. Neither the patient nor his family had a history of congenital hemolytic anemia. His Abbreviations: kb, kilobase(s); nt, nucleotide(s).