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Gene editing has revealed how dyskeratosis congenita (DC) impairs the formation of blood cells, according to research published in Stem Cell Reports.
The discovery has opened up new lines of investigation into how to treat DC, which is characterized by shortened telomeres.
“Lengthening telomeres seems like a logical way to help these patients, but it could possibly come with its own set of problems,” said study author Luis F.Z. Batista, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We would worry about encouraging cancer formation, for example, as high levels of the protein that lengthens telomeres—telomerase—are commonly found with cancer. But if we could find a way to block the signaling pathways that short telomeres activate—that specifically lead to the problems in blood cell formation—it could allow these patients to continue making blood cells.”
With this in mind, Dr Batista and his colleagues used CRISPR to edit into human embryonic stem cells a pair of mutations associated with DC— DKC1_A353V and TERT_P704S. These cells reproduced the telomere-shortening defect seen in patients with DC.
With this model, the researchers showed how the telomere defect leads to the gradual loss of blood cell formation and how blocking the downstream effects of the defect can reverse this loss, leading to normal production of blood cells.
Blocking this signaling pathway did not lengthen telomeres or stop their shortening, but it allowed the manufacturing of different types of blood cells to continue.
The researchers also made a discovery that provides a distinction regarding the detrimental effect of short telomeres during early development. The team found the defect did not hinder primitive hematopoiesis, but it did impair definitive hematopoiesis.
“This was tremendously interesting from a developmental biology perspective as well as from a disease modeling perspective,” said study author Christopher M. Sturgeon, PhD, of the Washington University School of Medicine. “We now have a platform to really dig deeper into understanding the mechanisms behind some forms of bone marrow failure.”
The researchers implicated high levels of the protein p53 as one of the signals that leads to the drop in definitive hematopoiesis.
“P53 is thought of as a guardian of the genome,” Dr Batista noted. “Mutations that disable p53 are associated with different types of cancer. Because of this, we would not consider directly trying to block p53 in these patients.”
“But what this study provides is proof-of-concept that this pathway is involved in this response. So we now are looking for ways to block the pathway further downstream without necessarily blocking p53 directly.”
Drs Batista and Sturgeon recently received a grant from the Department of Defense to investigate the pathway. The pair believes the strategy used in this study could be relevant for other bone marrow failure syndromes as well, such as Fanconi anemia and aplastic anemia. 
Gene editing has revealed how dyskeratosis congenita (DC) impairs the formation of blood cells, according to research published in Stem Cell Reports.
The discovery has opened up new lines of investigation into how to treat DC, which is characterized by shortened telomeres.
“Lengthening telomeres seems like a logical way to help these patients, but it could possibly come with its own set of problems,” said study author Luis F.Z. Batista, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We would worry about encouraging cancer formation, for example, as high levels of the protein that lengthens telomeres—telomerase—are commonly found with cancer. But if we could find a way to block the signaling pathways that short telomeres activate—that specifically lead to the problems in blood cell formation—it could allow these patients to continue making blood cells.”
With this in mind, Dr Batista and his colleagues used CRISPR to edit into human embryonic stem cells a pair of mutations associated with DC— DKC1_A353V and TERT_P704S. These cells reproduced the telomere-shortening defect seen in patients with DC.
With this model, the researchers showed how the telomere defect leads to the gradual loss of blood cell formation and how blocking the downstream effects of the defect can reverse this loss, leading to normal production of blood cells.
Blocking this signaling pathway did not lengthen telomeres or stop their shortening, but it allowed the manufacturing of different types of blood cells to continue.
The researchers also made a discovery that provides a distinction regarding the detrimental effect of short telomeres during early development. The team found the defect did not hinder primitive hematopoiesis, but it did impair definitive hematopoiesis.
“This was tremendously interesting from a developmental biology perspective as well as from a disease modeling perspective,” said study author Christopher M. Sturgeon, PhD, of the Washington University School of Medicine. “We now have a platform to really dig deeper into understanding the mechanisms behind some forms of bone marrow failure.”
The researchers implicated high levels of the protein p53 as one of the signals that leads to the drop in definitive hematopoiesis.
“P53 is thought of as a guardian of the genome,” Dr Batista noted. “Mutations that disable p53 are associated with different types of cancer. Because of this, we would not consider directly trying to block p53 in these patients.”
“But what this study provides is proof-of-concept that this pathway is involved in this response. So we now are looking for ways to block the pathway further downstream without necessarily blocking p53 directly.”
Drs Batista and Sturgeon recently received a grant from the Department of Defense to investigate the pathway. The pair believes the strategy used in this study could be relevant for other bone marrow failure syndromes as well, such as Fanconi anemia and aplastic anemia.
Gene editing has revealed how dyskeratosis congenita (DC) impairs the formation of blood cells, according to research published in Stem Cell Reports.
The discovery has opened up new lines of investigation into how to treat DC, which is characterized by shortened telomeres.
“Lengthening telomeres seems like a logical way to help these patients, but it could possibly come with its own set of problems,” said study author Luis F.Z. Batista, PhD, of the Washington University School of Medicine in St. Louis, Missouri.
“We would worry about encouraging cancer formation, for example, as high levels of the protein that lengthens telomeres—telomerase—are commonly found with cancer. But if we could find a way to block the signaling pathways that short telomeres activate—that specifically lead to the problems in blood cell formation—it could allow these patients to continue making blood cells.”
With this in mind, Dr Batista and his colleagues used CRISPR to edit into human embryonic stem cells a pair of mutations associated with DC— DKC1_A353V and TERT_P704S. These cells reproduced the telomere-shortening defect seen in patients with DC.
With this model, the researchers showed how the telomere defect leads to the gradual loss of blood cell formation and how blocking the downstream effects of the defect can reverse this loss, leading to normal production of blood cells.
Blocking this signaling pathway did not lengthen telomeres or stop their shortening, but it allowed the manufacturing of different types of blood cells to continue.
The researchers also made a discovery that provides a distinction regarding the detrimental effect of short telomeres during early development. The team found the defect did not hinder primitive hematopoiesis, but it did impair definitive hematopoiesis.
“This was tremendously interesting from a developmental biology perspective as well as from a disease modeling perspective,” said study author Christopher M. Sturgeon, PhD, of the Washington University School of Medicine. “We now have a platform to really dig deeper into understanding the mechanisms behind some forms of bone marrow failure.”
The researchers implicated high levels of the protein p53 as one of the signals that leads to the drop in definitive hematopoiesis.
“P53 is thought of as a guardian of the genome,” Dr Batista noted. “Mutations that disable p53 are associated with different types of cancer. Because of this, we would not consider directly trying to block p53 in these patients.”
“But what this study provides is proof-of-concept that this pathway is involved in this response. So we now are looking for ways to block the pathway further downstream without necessarily blocking p53 directly.”
Drs Batista and Sturgeon recently received a grant from the Department of Defense to investigate the pathway. The pair believes the strategy used in this study could be relevant for other bone marrow failure syndromes as well, such as Fanconi anemia and aplastic anemia.