High‐level induction of fetal haemoglobin by pomalidomide in β‐thalassaemia/HbE erythroid progenitor cells

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155942/1/bjh16670.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155942/2/bjh16670_am.pd

Reactivation of a developmentally silenced embryonic globin gene

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues

An international registry of survivors with Hb Bart's Hydrops Fetalis Syndrome

Hb Bart's Hydrops Fetalis Syndrome (BHFS) resulting from α0-thalassemia is considered a universally fatal disorder. However, over the last three decades improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective we analyze the available clinical information to document the natural history of BHFS. In future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period, however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ~40% being severely affected in terms of weight and ~50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and co-morbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies

An international registry of survivors with Hb Bart's Hydrops Fetalis Syndrome

Hb Bart's Hydrops Fetalis Syndrome (BHFS) resulting from α0-thalassemia is considered a universally fatal disorder. However, over the last three decades improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective we analyze the available clinical information to document the natural history of BHFS. In future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period, however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ~40% being severely affected in terms of weight and ~50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and co-morbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies