DOI: 10.1182/blood.2023022190 ISSN: 0006-4971

Elevating fetal hemoglobin - recently discovered regulators and mechanisms

Gerd A. Blobel, Eugene Khandros

It has been known for over half a century that humans produce different forms of hemoglobin, a tetramer of α- and β-like hemoglobin chains, throughout ontogeny. The switch from fetal to adult hemoglobin occurs around the time of birth when erythropoiesis shifts from the fetal liver to the bone marrow. Naturally, diseases caused by defective adult β-globin genes, such as sickle cell disease and β-thalassemia manifest themselves as production of fetal hemoglobin fades. Reversal of this developmental switch has been a major goal to treat these diseases and has been a driving force to understand its underlying molecular biology. Several review articles have illustrated the long and at times arduous paths that led to the discovery of the first transcriptional regulators involved in this process. Here we survey recent developments, spurred by the discovery of CRISPR tools that enabled for the first time high throughput genetic screens for new molecules that impact the fetal to adult hemoglobin switch. Numerous opportunities for therapeutic intervention thus came to light, offering hope for effective pharmacologic intervention for patients for whom gene therapy is out of reach.

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