Page 10 - Haematologica April 2020

Editorials
GATA1 gets personal
Anna Rita Migliaccio
Dipartimento di Scienze Biomediche e NeuroMotorie, Alma Mater Studiorum - Università di Bologna, Bologna and Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai, New York, NY, USA
E-mail: ANNA RITA MIGLIACCIO - annarita.migliaccio@unibo.it or annarita.migliaccio@mssm.edu doi:10.3324/haematol.2019.246355
Until the beginning of the 20th century, physicians had very few drugs at their disposal to assist them in their fight against disease. The blooming of chemistry into the new field of pharmacology completely revolutionized the concept of “treatment” in medicine. Pharmacology made a large array of chemicals available to physicians and this greatly improved their ability to treat or at least to halt the progression of numerous dis- eases. The synthesis of new effective chemical entities drove an optimistic belief that it would soon be possible to produce a “compound” to specifically cure every “dis- ease”. This belief has been tamed by the fact that, in recent years, the rate of discovery of new effective drugs has greatly decreased. The current consensus in the field is that pharmacology has exhausted its potential, and that any further progress in our ability to cure will be driven by being able to match the “treatments” with the “driver genetic lesions” and/or by personalizing the “treatment modality”, including optimization of the supportive treat- ments, to the “genetic and life-style” profile of the patient. This awareness has given rise to the develop- ment of the novel fields of precision1 and/or personal- ized2-4 medicine.
One of the most common consequences of the chemotherapy used to treat cancer is a severe and poten- tially lethal anemia which is treatable by blood transfu- sion, which represents an essential part of modern patient care. Transfusion has become a safe and widely available therapy thanks to the discovery of the major blood types by Karl Landsteiner, who received the Nobel price in 1930, and by the establishment of national and international blood banks in the 1940-1950s.5 Blood, however, is a lim- ited human resource, and although in western countries the blood supply is currently sufficient, in developing countries, the supply rarely meets existing needs.6 Furthermore, changes in human demographics predict a progressive increase in the population >60 years of age, restricting the pool of eligible donors, and increasing the blood requirements needed to support advanced surgical procedures and medical treatments in older individuals. This means that, even in industrialized countries, by as early as 2050, the blood supply may no longer be ade- quate.7 Additional challenges are presented by the out- breaks of novel infective diseases that increase the num- bers of tests a transfusion product must undergo before it can be considered safe and by the awareness that the shelf-life of blood products may be much shorter than pre- viously foreseen, which increases the number that go to waste. These challenges are posing an exponential burden to the economic and social costs of producing blood. The transfusion medicine community is aware of these chal- lenges and the need to ensure an adequate blood supply that is safe and affordable in order to meet the clinical
needs of the 21st century. More stringent and personalized criteria are, therefore, being implemented to define the patient populations in need of transfusion. These criteria are essential for evidence-based calculations of the blood products required at any given time, to reduce waste, and, therefore, the availability and costs of this therapy.
Human populations vary enormously in the number and biophysical properties of the red blood cells (RBC) present in the circulation and in the ability to recover from blood loss. The genetic basis of this variability has been the subject of several Genome Wide Association Studies (GWAS). These have identified several single nucleotide polymorphisms (SNP). These are regions of the DNA which do not affect the coding sequence of a gene, but rather the efficiency of its mRNA transcription and/or translation, and ultimately regulate the final protein con- tent which predicts, among other factors, the genetic basis of RBC variability. Most of the SNP associated with inher- ited erythroid traits identified so far are located in the putative regulatory regions of cKIT, the gene which encodes the receptor for stem cell factor, the growth factor which, in combination with erythropoietin, regulates RBC production. These SNP lie close to a prominent DNase hypersensitive region approximately 115 kb upstream of cKIT and are associated with the variability in RBC counts, mean RBC volume, and mean RBC hemoglobin content observed in the normal population.8,9 However, so far these studies have failed to drive personalized medi- cine strategies, for example, by identifying biomarkers for risk stratification of patients subjected to erythroid-related therapies. Surprisingly, these studies did not recognize SNP associated with GATA1.
GATA1 is a transcription factor which regulates the maturation of erythroid cells in a concentration-specific fashion. It is encoded by a gene, GATA1, located both in mice and men on the non-autosomal region of the X chro- mosome.10 Therefore, males are hemizygote for the maternal GATA1 allele while, due to the Lyonization effect, the hematopoietic stem cells of females are a mosa- ic of cells carrying either the maternal or the paternal allele in an active configuration. GATA1 is so important for ery- thropoiesis that mice lacking this gene die in utero from severe anemia and thrombocytopenia. Genetic alterations leading to a dysfunctional GATA1 protein have been iden- tified in several diseases:10 (i) point mutations in the coding sequences of the gene impairing, directly or indirectly, the DNA binding ability of the protein were detected in X- linked disorders associated with erythroid and/or megakaryocyte/neutrophil phenotype; (ii) deletions of the regulatory regions of the gene that eliminate a transcrip- tion start site required for the transcription of the mRNA encoding the full length form of the protein, making the cells hypomorphic for GATA1 protein, are associated with
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haematologica | 2020; 105(4)