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Researchers identify previously unknown cause of SCID
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Newborn screening led to the identification of mutant BCL11B as a previously unknown cause of severe combined immunodeficiency, according to study results presented in The New England Journal of Medicine.
“We identified a mutation in the DNA binding site of a transcription factor (BCL11B) that has been reported to either attenuate or promote cancer progression, depending on the context,” David L. Wiest, PhD, deputy chief scientific officer at Fox Chase Cancer Center, told HemOnc Today. “Our data reveal that this mutation does not merely block DNA binding, but also redirects BCL11B to new gene targets, which may provide insight into its dual function in cancer.”
Early diagnosis of severe combined immunodeficiency (SCID) through newborn screening is essential to help diagnose the disease before the development of infections and to hasten the identification of a donor for allogeneic hematopoietic stem cell transplantation. Further, screening can lead to the identification of factors that cause T-cell lymphopenia, which characterizes SCID.
As a result of newborn screening of T-cell–receptor excision circles, researchers identified SCID in a newborn boy before the onset of infections. The patient had “leaky” SCID, indicating there was a minimal degree of preserved immune function, as well as craniofacial and dermal abnormalities and the absence of a corpus callosum.
The patient underwent allogeneic HSCT, which fully corrected his immune deficit.
Researchers conducted exome sequencing in the patient and his parents to identify a heterozygous de novo missense mutation, p.N441K, in BCL11B.
Wiest and colleagues then conducted a functional analysis of the candidate gene in human hematopoietic stem cells and zebrafish embryos; the transparency of zebrafish embryos enables researchers to observe abnormalities.
Overall, researchers found that the BCL11B protein had dominate negative activity, which prevented wild-type BCL11B from binding DNA, leading to the cessation in T-cell lineage development and disruption of hematopoietic stem cell migration.
This represents a previously unknown function of BCL11B, the researchers wrote.
“The role of BCL11B in supporting the commitment of thymic progenitors to the T-cell lineage has been studied in other models, including the mouse; however, a requirement for BCL11B in the development of prethymic progenitors was not previously known,” they wrote. “We found BCL11B to be essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of receptors CCR7 and CCR9, which direct the movement of progenitors in mammals from the bone marrow to the thymus.”
When the patients’ abnormalities were recapitulated in bcl11b–deficient zebrafish they were reverse by ectopic expression of functionally intact human BCL11B, but not mutant BCL11B.
“Identifying the causative gene mutations in SCID may lead to the ultimate in personalized medicine,” Wiest said in a press release. “This study is a great reminder of the interconnectedness of medical research. Understanding basic cellular function is key to ultimately prevailing over cancer.”
Additional research is necessary, Wiest told HemOnc Today.
“We intend to explore the molecular basis by which this mutation alters BCL11B function in development, as well as in cancer,” he said. “In addition, we will exploit our gene discovery pipeline to explore the utility of genome editing as a treatment for SCID.” – by Alexandra Todak
For more information:
David L. Wiest, PhD, can be reached at 333 Cottman Ave., Fox Chase Cancer Center, R390 Philadelphia, PA 19111.
Disclosure: Wiest reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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