Thesis Preamble translation, July 1, 2013²

Β-thalassemia is one of the most common genetic diseases in the world, along with sickle cell anemia. During β thalassemia major, there is more or very little production of β-globin chains which leads to an excess of free α-globin chains, which normally associate with β-globin chains for form the hemoglobin tetramer. The synthesis of hemoglobin (hemoglobinization) takes place in the bone marrow, during terminal erythroid differentiation. Excess α-globin chains in mature erythroblasts cause their precipitation, toxic to the cell, and is associated with arrest of maturation and death by apoptosis of these cells. This results in profound anemia in patients, which must be transfused monthly throughout their life. The mechanisms of α-globin chain toxicity to mature erythroblasts are not fully understood. However
Few reviews of the literature have been published on ineffective erythropoiesis of βthalassemia over the past fifteen years, but these writings very often confuse the physiopathological mechanisms of α-globin toxicity on red blood cells (the most numerous studies) with toxicity on erythroblasts, little studied. This deserves a critical presentation of the data in the literature which will be made in the introduction.

Our work focused on the role of the Hsp70 chaperone during the ineffective erythropoiesis of major β-thalassemias. The ubiquitous role of this chaperone is to prevent badly formed proteins from being toxic to cells. Hsp70 being expressed constitutively in high concentration during erythropoiesis, it made sense to investigate its involvement in a disease where toxic peptides accumulate in erythroblasts.

In the first part of this thesis, we wanted to start by presenting the characteristics of the Hsp70 protein, of which our team is, to date, the only one in the world to study its role in human erythropoiesis. We will therefore summarize 10 years of studies of this protein in our laboratory, highlighting the well-established data and the gray areas that persist. We will then present the main phases of physiological erythropoiesis, focusing on the synthesis of hemoglobin during erythroid maturation and on the fundamental transcription factor of erythropoiesis GATA-1, protected in the nucleus by Hsp70. We will end this introduction with a critical analysis of the literature on the ineffective erythropoiesis of β-thalassemia, which was also the subject of a publication proposed in the appendix.