Alpha‐ and beta‐synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia

Abstract

b b-thalassemias are characterized by an imbalance of globin chains with an excess of a-chains which precipitates in erythroid precursors and red blood cells (RBCs) leading to inefficient erythropoiesis. The severity of the disease correlates with the amount of unpaired achains. Our goal was to develop a simple test for evaluation of the free a-hemoglobin pool present in RBC lysates. Alpha-Hemoglobin Stabilizing Protein (AHSP), the chaperone of a-Hb, was used to trap excess aHb. A recombinant GST-AHSP fusion protein was bound to an affinity micro-column and then incubated with hemolysates of patients. After washing, the a-Hb was quantified by spectrophotometry in the elution fraction. This assay was applied to 54 patients: 28 without apparent Hb disorder, 20 b-thalassemic and 6 a-thalassemic. The average value of free a-Hb pool was 93 ± 21 ppm (ng of free a-Hb per mg of Hb subunits) in patients without Hb disorder, while it varies from 119 to 1,756 ppm, in b-thalassemic patients and correlated with genotype. In contrast, the value of the free a-Hb pool was decreased in a-thalassemic patients (65 ± 26 ppm). This assay may help to characterize b-thalassemia phenotypes and to follow the evolution of the globin chain imbalance (a/b+c ratio) in response to treatment.b-thalassemias (b-thal) are inherited autosomal diseases characterized by a decreased or abolished b-globin chain biosynthesis [1]. During the transition of g to b globin expression in the first year of life, the clinical severity is mainly related to the ratio a/b1g which indicates the level of chain disequilibrium. b-thal are generally classified as minor, intermediate, or major phenotype, and encompass a wide clinical spectrum ranging from asymptomatic carriers to forms that can be lethal in the absence of extensive treatment. Different factors can modulate the severity of this disease [2] such as the magnitude of the decrease of the b globin synthesis, for example hemoglobin E (Hb E b26Glu?Lys) [3], or with the co-inheritance of (i) an a-thalassemia (a-thal) [4], (ii) a triplicated a-globin gene [5] or (iii) a low but variable residual capacity of g globin production which can have the phenotype of a hereditary persistence of fetal Hb (Hb F a 2 g 2 ) [6].The imbalance between a and non a-globin (g1d1b) synthesis was established by radioactive in vitro biosynthesis of globin chains from reticulocytes or of bone marrow of b-thalassemic patients [7][8][9][10]. This imbalance leads to an excess of highly unstable free a-hemoglobin (a-Hb), precipitating on the cell membrane and acting as active oxidants causing apoptosis and inefficient erythropoiesis [1,11]. The severity of b-thal is directly correlated with the degree of imbalance as quantified by the amount of unbound a-globin chain [12]. Many studies have shown that one observes a soluble a chain fraction present in the cytosolic RBC and an insoluble a chain fraction in the membrane of b-thalassemic erythrocytes [13,14]. Because of technical difficulties and the burden of using radioactive materials, ...

A critical role for alpha-synuclein in development and function of T lymphocytes

“…Maturation of megakaryocytes leads to increased expression of α-synuclein with a concomitant down-regulation of β-synuclein (Hashimoto et al, 1997). Consistent with these findings, α-synuclein has been shown to be expressed by blasts of acute erythroid leukemia and acute megakaryoblastic leukemia, whereas its expression is reduced in megakaryocytes of myeloproliferative disorders (Maitta et al, 2011). Expression of β-synuclein, on the other hand, is noted only in the blasts of acute megakaryoblastic leukemia (Maitta et al, 2011).…”

Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson's disease

“…CLPs can differentiate into T, B and natural killer (NK) cells but not myeloid cells, while CMPs give rise to all myeloid lineage cells via megakaryocyte/ erythrocyte (MEPs) or granulocyte/macrophage progenitors (GMPs). It was recently shown that α-synuclein is present in megakaryocytes, platelets, erythroid precursors, and erythrocytes, while its expression is reduced in megakaryocytes of myeloproliferative neoplasms (Maitta et al, 2011). Moreover, it was found to be a specific marker of acute megakaryoblastic leukemia subtype M7 (AML M7) suggesting that α-synuclein could play a role in the pathogenesis of some hematological neoplasms.…”

γ-Synuclein Is a Promising New Marker for Staining Reactive Follicular Dendritic Cells, Follicular Dendritic Cell Sarcoma, Kaposi Sarcoma, and Benign and Malignant Vascular Tumors

“…4,23 Using immunohistochemical staining of normal bone marrow, we have recently confirmed and extended these observations to neoplastic bone marrow, where a-synuclein was expressed by erythroid precursors in acute erythroid leukemia and by megakaryoblasts in acute megakaryoblastic leukemia, but not by myeloblasts in acute myeloid leukemia. 18 In contrast, we detected g-synuclein in the endothelial cells lining the sinuses and blood vessels of the bone marrow but not in any hematopoietic cell lineages. 18 Although the expression of g-synuclein by vascular endothelial cells has been described in nonlymphoid tissues, 17 the tumors of lymphatic and vascular origin have not been studied.…”

“…18 In contrast, we detected g-synuclein in the endothelial cells lining the sinuses and blood vessels of the bone marrow but not in any hematopoietic cell lineages. 18 Although the expression of g-synuclein by vascular endothelial cells has been described in nonlymphoid tissues, 17 the tumors of lymphatic and vascular origin have not been studied. Therefore, we immunohistochemically stained a comprehensive panel of benign and malignant lymphoid tissues and spindle cell neoplasms (SSNs) for the expression of g-synuclein.…”