By David P. Steensma, MD

2009-12-07

Among the many developmental milestones that infants must achieve, the most important hematologic event is invisible to doting parents: the switch from production of fetal hemoglobin to adult hemoglobin, normally complete by the end of the first year of post-natal life.

This transformation is scientifically interesting because of the insights that hemoglobin switching can offer into mammalian gene regulation. From a clinical standpoint, it is also crucial to understand this switch in detail, since higher levels of fetal hemoglobin are associated with a milder clinical course in sickle cell disease. Treatments that re-activate silenced γ globin expression (fetal hemoglobin is composed of two α globin subunits and two γ globin subunits) could prevent a series of devastating disease-associated complications in patients with sickle cell disease and related hemoglobin disorders.

The human β globin gene cluster on chromosome 11 and its mammalian homologs are the most well-studied gene regions in all of biology. Hemoglobin switching itself has been the topic of scientific conferences held biennially since 1978, organized by George Stamatoyannopoulos (University of Washington) and like-minded colleagues. Yet despite more than 25 years of detailed molecular analysis, the mechanisms underlying switching have proven frustratingly difficult to define.

In yesterday’s Plenary Session, Dr. Jian Xu, from Dr. Stuart Orkin’s laboratory at Children’s Hospital and the Dana-Farber Cancer Institute in Boston, discussed exciting new findings with respect to BCL11A, a zinc-finger protein that is a major repressor of γ globin gene expression (abstract #5).

BCL11A was first identified as a potentially important factor in globin regulation by way of genome-wide association studies, such as one published in Nature Genetics in 2007 by Professor Swee Lay Thein’s group at King’s College in London, as well as analyses by Dr. Orkin’s group and their collaborators in Italy, who compared single nucleotide polymorphism variation between populations that express fetal hemoglobin at different levels. A polymorphism in an intron of the gene on chromosome 2 that encodes BCL11A turned out to be strongly correlated with γ globin expression. Subsequent experiments performed in the Orkin laboratory demonstrated that in vitro shRNA-mediated knockdown of BCL11A expression in human erythroid progenitor cells massively increased fetal hemoglobin production, as expected if BCL11A is a major mediator of γ globin silencing.

Dr. Xu described a series of mechanistic experiments in transgenic mice expressing a human β globin gene cluster (β-locus mice) — experiments that collectively established BCL11A as a major transcriptional regulator of developmental control of globin switching and of γ globin silencing in adults. Some of these important results were initially published by Harvard MD-PhD student Vijay Sankaran, MPhil, MS, Dr. Xu, and colleagues in Dr. Orkin’s laboratory in Nature on August 27, 2009, and in Science on December 11, 2008.

“This is a promising finding for the globin regulation field, as the mouse work confirms BCL11A has a striking effect on γ globin expression, to a greater extent than any other factor previously described,” stated Professor Bill Wood, a fetal hemoglobin expert from the Weatherall Institute of Molecular Medicine in Oxford. “A trans-acting factor involved in switching like BCL11A is the sort of regulatory factor that many groups have been seeking for a long time.”

“BCL11A appears to be a critical transcription factor driving the switching process and mediating γ globin suppression in adults,” said Dr. Xu. “The human population work started by Vijay Sankaran identified BCL11A as a likely candidate for altering fetal hemoglobin levels, and the mouse models and other work that I described in the Plenary Session provide essential evidence supporting the importance of BCL11A in regulating human globin expression. Given the magnitude of the effects on expression, this transcription factor must be a central regulator of hemoglobin switching.”

While the Plenary Session highlights the best work at each year’s annual meeting, it is rare that presentations provide an answer to a question that has been asked by so many for so long as the problem of fetal hemoglobin regulation. Yesterday, the audience had the opportunity to hear Dr. Xu discuss what could be a landmark discovery in the history of hematology.

Dr. Steensma indicated no relevant conflicts of interest.

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