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BCL11A controlled hemoglobin, silenced fetal hemoglobin expression in adult erythroid cells
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51st ASH Annual Meeting
The inactivation of the BCL11A gene allowed for the increased expression of gamma-globin (the fetal form of hemoglobin) during late gestation in embryonic mice genetically engineered to carry a complete human beta-globin gene cluster capable of producing adult hemoglobin, according to data presented by Stuart Orkin, MD, at the the 51st ASH Annual Meeting.
“If we down regulate the expression of this protein then we can reactivate expression of the hemoglobin in the fetal stage — this response is quite robust,” Orkin, of the department of pediatric oncology at the Dana Farber Cancer Institute, said during a press conference.
It is hypothesized that if patients with sickle cell disease could continue production of the fetal hemoglobin and produce less of their defective adult sickle hemoglobin, many of their complications could be reduced.
Therefore, researchers set out to assess the mechanisms of fetal hemoglobin switching and silencing as a means for targeted reactivation of gamma-globin gene expression in adults. Researchers used conditional inactivation of BCL11A through hematopoietic- and erythroid-specific Cre-alleles to address the contribution of BCL11A to gamma-globin silencing.
Results indicated that inactivation of the BCL11A gene led to a robust expression of gamma-globin during late gestation. Tissue-specific deletion of BCL11A in the adult mice resulted in an increase of more than 1,000 fold in gamma-globin gene expression in the bone marrow erythroblasts of the experimental mice. This persisted for 25 weeks.
“The surprise here is that BCL11A is really the dominant controller of the switch in development. I think there is a realistic possibility of using this as a target to eventually develop drugs that would reactive the hemoglobin in the adult,” Orkin said.
“This is still in the prelimary phase in terms of the science, but for the first time we have a molecule that we can point to which controls the switch process and by learning how that functions and the precise mechanism I think we will be in a much better position when it comes to designing targeted therapies in the future, which is the ultimate goal.” – by Jennifer Southall
For more information:
- Orkin SJ. #5. Presented at: 51st ASH Annual Meeting and Exposition; Dec. 4-8, 2009; New Orleans.
This abstract is very exciting both from a basic science point of view and for its potential therapeutic impact. The control of hemoglobin switching has been the holy grail of hemoglobin studies because of its promise for treating sickle cell disease and beta thalassemia. This is the first paper that has shown not only a mechanism for the gamma-to-beta switch but also a molecular intervention that derepresses the gamma-globin gene. That being said, it is still a long way from a mouse to a human. The other potential barrier to clinical application is the possibility that interference with BCL11A could have other, undesirable effects. The gene product is also involved in normal lymphocyte development and, when overexpressed or part of an oncogenic translocation, with B-cell lymphoma.
- Peter Newburger, MD
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