Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired ␣-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired ␣-thalassemia are now recognized: acquired deletion of the ␣-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic downregulation of ␣-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of ␣-thalassemia arising in a clonal myeloid disorder, and we discuss how ATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.
IntroductionFor more than 4 decades, the synthesis of hemoglobin during erythropoiesis has served as an excellent model for understanding mammalian gene regulation. A diverse repertoire of naturally occurring mutations of the globin genes has enabled researchers to use this system to establish many of the general principles underlying human molecular genetics and, in particular, to advance our understanding of molecular hematology. 1 Although nearly all globin mutations characterized to date have been cis-acting defects, it has recently emerged that globin synthesis may also be altered by trans-acting mutations involving erythroid-specific and general transcriptional regulators. [2][3][4] It has long been recognized that patients with hematologic malignancy and abnormal erythropoiesis may also acquire changes in hemoglobin structure or synthesis, but the molecular basis of such abnormalities remained obscure. However, recent studies of patients with myelodysplasia who acquire thalassemia have identified somatic mutations in a known trans-acting regulator of globin gene expression, ATRX (␣-thalassemia mental retardation X-linked, named after the phenotype associated with germline mutations in the gene). 5,6 Although these new observations will undoubtedly increase our understanding of how globin gene expression is normally controlled, they may also point to common genetic or epigenetic mutations that contribute to the development or progression of myelodysplasia.
Normal structure and expression of globin gene clustersThe synthesis of hemoglobin is controlled by 2 developmentally regulated multigene clusters: the ␣-like globin cluster on chromosome 16 (5Ј--␣2-␣1-3Ј) and the -like globin cluster on chromosome 11 (5Ј-⑀-G␥-A␥-␦--3Ј) ( Figure 1). Coordinated expres...