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The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.
They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.
The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow
normally.
The team relayed these findings in Stem Cell Reports.
“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings also raise a number of important questions, so there is a lot more to be done.”
For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.
The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.
Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.
However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.
The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.
So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.
After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.
The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.
Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.
“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”
The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.
The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice. 
The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.
They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.
The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow
normally.
The team relayed these findings in Stem Cell Reports.
“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings also raise a number of important questions, so there is a lot more to be done.”
For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.
The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.
Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.
However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.
The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.
So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.
After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.
The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.
Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.
“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”
The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.
The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice.
The protein kinase CHK1 may be a therapeutic target for Fanconi anemia (FA), according to researchers.
They studied induced pluripotent stem cells (iPSCs) derived from FA patients and found the FA DNA repair pathway was essential for the cells’ proliferation and survival.
The team also discovered that CHK1 played a “crucial” role in iPSCs’ sensitivity to accrued DNA damage, and inhibiting CHK1 allowed FA-deficient iPSCs to grow
normally.
The team relayed these findings in Stem Cell Reports.
“This study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options,” said study author Susanne Wells, PhD, of the Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings also raise a number of important questions, so there is a lot more to be done.”
For this study, Dr Wells and her colleagues used iPSCs reprogrammed from mature skin and connective tissue cells donated by FA patients. The cells had a defective FA DNA repair pathway.
The researchers studied the iPSCs in culture and injected them into humanized mouse models, monitoring their genetic, molecular, and developmental progression.
Even with defective FA DNA repair, the iPSCs retained their ability to transform into different tissues, and humanized mice injected with the defective cells started to form teratomas.
However, the DNA repair defect started to kill off the iPSCs by blocking cell division and causing apoptosis.
The researchers noticed that CHK1, which serves as a DNA regulatory checkpoint during cell division, was hyperactive in the iPSCs, which hastened their death.
So the team used pharmacologic inhibitors of CHK1 to block the hyperactive enzyme at a critical stage of the stem cell cycle. This allowed them to override what are usually unfixable errors in the FA repair pathway.
After targeted treatment, FA-pathway-deficient iPSCs resumed dividing and expanding normally.
The researchers said that, to their surprise, the resumption of cell growth occurred without what they had expected to be massive chromosome abnormalities. Because of this, they speculate that a compensating DNA repair process is engaged in the reinvigorated cells.
Because this unidentified repair process may also rescue the DNA repair defect in the different tissue types affected by FA, Dr Wells and her colleagues believe their study may point to an approach that treats all clinical manifestations of the disease, including anemia and cancer.
“A key question for us is, ‘What type of DNA repair kicks in under these conditions, and is it error-free or error-prone?’” Dr Wells explained. “A novel mode of emergency DNA repair might indeed be discovered in the [iPSCs]. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss. Otherwise, the cells would have died off very quickly.”
The researchers plan to follow up this study with additional testing in humanized and genetic mouse models. They said they will attempt to improve embryonic development and post-birth fitness in FA-pathway-deficient mice with timed application of a CHK1 inhibitor.
The team will monitor the mice as they age and use genetic sequencing to screen for disease-causing mutations. And they will look for evidence of a DNA repair process (either novel or existing) in the FA-deficient mice.