Clinical features and molecular analysis of acquired hemoglobin H disease

Abstract

The presence of hemoglobin H ( β 4), resulting from a deficiency of α-globin chain synthesis, was observed as an acquired characteristic in the red cells of five elderly patients with myeloproliferative disorders or preleukemia. The variability in amount of hemoglobin H and in the α β globin synthesis ratios in these patients is most likely explained by the relative proportions of normal and abnormal cell populations in the peripheral blood, since some reticulocyte fractions with balanced α β globin synthesis ratios and others with almost no detectable α-chain production could be obtained from these patients. In one patient, the hemoglobin H virtually disappeared despite continuing disease. The amount of cytoplasmic α-mRNA matched the proportion of α-chain synthesis and, in one patient, this was also true for nuclear RNA. However, extensive analysis of the α-globin gene complex by restriction endonuclease mapping revealed no detectable rearrangements of the normal gene organization in any of these patients, suggesting that transcription of each pair of α-globin genes on each chromosome 16 is defective. These observations have important implications for both the normal regulation of α-globin gene expression and the molecular basis of the underlying defect that is associated with the neoplastic transformation of these cells.