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mycosis fungoides
Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).
The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.
This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.
Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.
Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.
TNFR2 mutations
The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.
TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.
Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.
This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.
In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.
The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.
Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes. 
mycosis fungoides
Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).
The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.
This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.
Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.
Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.
TNFR2 mutations
The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.
TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.
Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.
This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.
In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.
The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.
Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes.
mycosis fungoides
Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).
The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.
This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.
Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.
Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.
TNFR2 mutations
The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.
TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.
Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.
This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.
In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.
The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.
Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes.