Deletion of the alpha-globin gene cluster as a cause of acquired alpha-thalassemia in myelodysplastic syndrome

Rarely, myelodysplastic syndrome (MDS) is complicated by an acquired form of alpha-thalassemia (alpha-thalassemia in myelodysplastic syndrome ATMDS]) characterized by hypochromic, microcytic, anisopoikilocytic red blood cells with hemoglobin H (HbH) inclusions. Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH. The alpha-globin genes themselves have appeared normal in all ATMDS patients studied to date. Here we characterize the molecular defect in a unique MDS patient with rare HbH inclusions in which an abnormal clone lost a greater than 1.9-Mb segment of the telomeric region of the short arm of one allele of chromosome 16, including both alpha-globin genes. Red blood cell changes associated with this acquired somatic genotype (--/alpha alpha) are surprisingly severe, demonstrating that a minor globin chain imbalance may be unexpectedly deleterious during the abnormal erythropoiesis that occurs in the context of MDS.