Myeloproliferative syndrome with sideroblastic anemia and acquired hemoglobin H disease

Abstract

Hemoglobin H disease usually occurs as a result of inheritance of the genes for alpha thalassemia; however, occasionally patients acquire hemoglobin H in association with hematologic malignancy. This report concerns a 63-year-old Filipino man with a myeloproliferative syndrome with marked thrombocytosis and apparently acquired hemoglobulin H disease. The patient had hemolytic anemia, dimorphic red blood cells (RBC) and abundant ringed sideroblasts in the marrow. The peripheral blood contained 27% hemoglobin H and about two-thirds of his RBC had hemoglobin H inclusion bodies. There was no previous history of anemia or evidence of thalassemia in two siblings or nine adult children of the patient. In vitro studies of globin chain synthesis documented markedly decreased production of alpha globin with alpha/beta biosynthetic ratios of 0.05 in peripheral blood reticulocytes and 0.10 in bone marrow cells. The relative concentration of mRNA for alpha globin was approximately 20-fold less than that of beta globin, apparently accounting for the deficiency in alpha globin synthesis.

Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes.

“…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).…”

“…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).…”

“…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)(2)(3), sideroblastic anemia (4)(5)(6), myelofibrosis (7,8), chronic myelogenous leukemia (9), acute leukemia (10)(11)(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.…”

Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe β thalassemia

“…Hematologic disorders having many features in common with ␣ thalassemia, expressed with the phenotype of Hb H disease, have been observed as acquired abnormalities in patients with a wide variety of other blood diseases, including acute lymphoblastic leukemia [27], erythroleukemia [28,29], adult CML [30], sideroblastic anemia [31,32], myelofibrosis [33,34], and other forms of myeloproliferative disease [35,36].…”

“…Efforts to identify the underlying molecular abnormality in these acquired Hb H disease syndromes have been only partly successful. Studies of several of these patients [32,36,37] have shown markedly decreased levels of ␣chain mRNA in their hemoglobin-synthesizing cells. However restriction enzyme mapping studies of their ␣globin and -globin genes were unrevealing of any abnormality [36,37].…”