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

Abstract

IntroductionThe myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by ineffective clonal hematopoiesis, acquired genomic instability, and variable risk for transformation to acute leukemia. 1 Most patients with MDS have macrocytic or normocytic anemia, but occasional patients have microcytic red blood cell indices. 2 Rarely, MDS patients with striking hypochromia, microcytosis, and anisopoikilocytosis are found to have acquired hemoglobin H (HbH) disease (␣-thalassemia); this constellation of findings has been called ␣-thalassemia myelodysplastic syndrome (ATMDS). 3 In most patients with ATMDS, a substantial proportion of red blood cells contain HbH inclusions after supravital staining, and severely decreased ␣-globin chain synthesis is paralleled by diminished ␣-globin cytoplasmic and nuclear mRNA levels. 3,4 The common inherited forms of ␣-thalassemia are frequently a consequence of deletions or point mutations affecting the duplicated ␣-globin genes (␣␣/␣␣) on chromosome 16 or, less commonly, deletions of the remote regulatory elements that control ␣-globin expression. 5,6 Germline mutations of ATRX, an X-linked gene encoding a chromatin remodeling protein that regulates the expression of diverse genes, cause mild ␣-thalassemia associated with developmental abnormalities (ATR-X syndrome). 7 ATRX mutations down-regulate the expression of all 4 ␣-globin genes, but the ␣-globin cluster itself is normal.Recently, we have shown that acquired, somatic mutations in the ATRX gene can also underlie ATMDS syndrome. 8,9 To date, 12 unique pathologic ATRX mutations have been found in patients with typical features of ATMDS, including striking "thalassemic" blood pictures, substantial amounts (more than 10%) of HbH, and severely reduced ␣/␤ globin chain biosynthesis ratios. 8,9 However, we have also studied several patients with MDS who have hypochromic, microcytic, red blood cell morphology, but in whom HbH inclusions are only present in a small proportion of erythrocytes or cannot be detected at all. To date, none of these patients have been shown to have mutations in the ATRX gene; the underlying molecular defect remains unknown.Here we report acquired ␣-thalassemia and rare HbH inclusions in an MDS patient. In contrast to previously reported cases of ATMDS, an abnormal hematopoietic clone in this patient had an acquired deletion involving the telomeric region of one allele of chromosome 16, removing 2 of the 4 ␣-genes (ie, genotype ϪϪ/␣␣). This case illustrates a second, less severe mechanism by which ␣-thalassemia may occur as an acquired abnormality in the context of hematologic malignancy. Study designA 72-year-old white British man had microcytic, hypochromic anemia (hemoglobin count, 10.4 g/dL; mean corpuscular volume, 64 fL; mean corpuscular hemoglobin level, 21.7 pg) and neutropenia (leukocyte count, 4.8 ϫ 10 9 /L with 14.7% neutrophils). Two years earlier, he had undergone partial pneumonectomy for localized lung carcinoma; at that time complete blood count finding...

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

“…3). In one exception, the telomeric end of chromosome 16p, including the a-globin cluster, was deleted in a clonally restricted fashion as part of a complex MDSassociated karyotype with numerous large chromosomal rearrangements (Steensma et al 2004b).…”

Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies

“…In only a single instance has a lesion in this region been found: an MDS patient with a complex karyotype was recently found to have lost the telomeric region of 1 of 2 copies of chromosome 16 (acquired genotype: ϪϪ/␣␣) in a clonal fashion. 61 The patient had relatively mild anemia (his hemoglobin level was 10.4 g/dL in the absence of transfusion), and only 0.11% HbHcontaining red blood cells were detected, but the red blood cells were microcytic and hypochromic (MCV, 64 fL; MCH, 21.7 pg). Despite the relatively well-maintained hemoglobin level, the red blood cell morphology was more abnormal than one would expect to see with a constitutional loss of only 2 of the 4 ␣-globin genes.…”

Prevalence of erythrocyte haemoglobin H inclusions in unselected patients with clonal myeloid disorders

“…We have previously described two molecular aetiologies for ATMDS. Rarely, ATMDS can result from clonally‐restricted loss of the terminal portion of the short arm of chromosome 16, the genomic region containing the HBA cluster (Steensma et al , 2004b). Much more commonly, patients with ATMDS have somatic mutations in ATRX, an X‐linked chromatin‐associated factor with trans ‐acting effects on α globin expression (Gibbons et al , 2003; Steensma et al , 2004a).…”