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telomeres in green
Image by Claus Azzalin
Researchers say they have identified a mechanism by which defective telomere replication exacerbates tumor growth.
The team found that simultaneous inactivation of the telomere-binding factor POT1 and the tumor suppressor p53 accelerates the onset and increases the severity of T-cell lymphomas.
The research, published in Cell Reports, also suggests a possible way to fight these lymphomas—by targeting the ATR pathway.
The researchers knew that POT1 normally forms a protective cap around telomeres, stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.
In fact, POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of ATR, which triggers apoptosis.
However, recent research revealed recurrent mutations affecting POT1 in several cancers, including leukemia and melanoma.
“Somehow, those cells found a way to survive—and thrive,” said Eros Lazzerini Denchi, PhD, of The Scripps Research Institute in La Jolla, California.
“We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”
Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in p53.
“The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” Dr Lazzerini Denchi said.
When mutated, p53 overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. The mutant cells go on to proliferate and become aggressive tumors.
These findings led the researchers to consider a new strategy for killing these tumors.
They noted that all cells will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a drug that knocks out the remaining ATR could kill tumors without affecting healthy cells.
The team plans to investigate this approach in future studies.
“This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” Dr Lazzerini Denchi concluded. 
telomeres in green
Image by Claus Azzalin
Researchers say they have identified a mechanism by which defective telomere replication exacerbates tumor growth.
The team found that simultaneous inactivation of the telomere-binding factor POT1 and the tumor suppressor p53 accelerates the onset and increases the severity of T-cell lymphomas.
The research, published in Cell Reports, also suggests a possible way to fight these lymphomas—by targeting the ATR pathway.
The researchers knew that POT1 normally forms a protective cap around telomeres, stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.
In fact, POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of ATR, which triggers apoptosis.
However, recent research revealed recurrent mutations affecting POT1 in several cancers, including leukemia and melanoma.
“Somehow, those cells found a way to survive—and thrive,” said Eros Lazzerini Denchi, PhD, of The Scripps Research Institute in La Jolla, California.
“We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”
Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in p53.
“The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” Dr Lazzerini Denchi said.
When mutated, p53 overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. The mutant cells go on to proliferate and become aggressive tumors.
These findings led the researchers to consider a new strategy for killing these tumors.
They noted that all cells will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a drug that knocks out the remaining ATR could kill tumors without affecting healthy cells.
The team plans to investigate this approach in future studies.
“This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” Dr Lazzerini Denchi concluded.
telomeres in green
Image by Claus Azzalin
Researchers say they have identified a mechanism by which defective telomere replication exacerbates tumor growth.
The team found that simultaneous inactivation of the telomere-binding factor POT1 and the tumor suppressor p53 accelerates the onset and increases the severity of T-cell lymphomas.
The research, published in Cell Reports, also suggests a possible way to fight these lymphomas—by targeting the ATR pathway.
The researchers knew that POT1 normally forms a protective cap around telomeres, stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.
In fact, POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of ATR, which triggers apoptosis.
However, recent research revealed recurrent mutations affecting POT1 in several cancers, including leukemia and melanoma.
“Somehow, those cells found a way to survive—and thrive,” said Eros Lazzerini Denchi, PhD, of The Scripps Research Institute in La Jolla, California.
“We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”
Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in p53.
“The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” Dr Lazzerini Denchi said.
When mutated, p53 overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. The mutant cells go on to proliferate and become aggressive tumors.
These findings led the researchers to consider a new strategy for killing these tumors.
They noted that all cells will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a drug that knocks out the remaining ATR could kill tumors without affecting healthy cells.
The team plans to investigate this approach in future studies.
“This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” Dr Lazzerini Denchi concluded.