Sézary syndrome (SS), a rare and aggressive form of cutaneous T-cell leukemia, involves an unexpected degree of genomic alteration, including Janus kinase 1 (JAK1) mutations that appear to be sensitive to JAK inhibitors.
SÃ©zary syndrome (SS), a rare and aggressive form of cutaneous T-cell leukemia, involves an unexpected degree of genomic alteration, including Janus kinase 1 (JAK1) mutations that appear to be sensitive to JAK inhibitors, according to authors of a new study published in Nature Communications.1
“We basically found chromosomal chaos in all of our samples,” said coauthor Kojo Elenitoba-Johnson, MD, the C. Nowell, M.D. Professor and director of the Center for Personalized Diagnostics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “We did not expect the degree of genetic complexity that we found in our study.”2
The study revealed “frequent disruption of epigenetic modifiers, cell cycle regulators and subversion of signalling modules involved in T-cell receptor, chemokine, and cytokine signalling pathways critical for T-cell activation, survival and differentiation,” the coauthors reported.1
The researchers conducted an integrated gene-sequencing study using whole-genome and whole-exome sequencing, and genomic gene copy number analysis, for 80 SS sample genomes.
In addition to recurrent loss-of-function mutations in well-characterized tumor suppressor genes like TP53 and PTEN, they also found recurrent gain-of-function mutations in JAK1, JAK3, STAT3 and STAT5B, affecting 11% of the SÃ©zary syndrome cell genomes analyzed, and PLCG1 in 9% of genomes analyzed.
A preliminary drug-mutation matching assessment, found that the JAK1 mutation-harboring tumor cells were sensitive to JAK tyrosine kinase inhibitors. These results “highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS,” the coauthors reported.
“With knowledge like this, we can design clinical trials using JAK inhibitors for SS patients based on their JAK mutations,” noted Elenitoba-Johnson. “But this is just the start. These results highlight the genetic vulnerabilities that we can use in designing precision medicine therapies.”
The team also found recurrent loss-of-function and deletion mutations in genes like ARID1A, MLLs, SETDIA/B, and demethylase and DNA methyltransferase genes, which are involved in chromatin remodelling and histone modification. ARID1A deletions and loss-of-function mutations were found in 40.3% of the SÃ©zary syndrome cell genomes analyzed.
These represent “a striking profile of recurrent loss-of-function alterations in the forms of deletions and inactivating mutations targeting the epigenetic modification machinery,” the coauthors noted.1 “These results highlight the substantial contribution of epigenetic deregulation in the pathogenesis of SS and provide targeted insights to study the mechanisms of sensitivity and resistance to inhibitors of histone deacetylases and DNA methyltransferases in SS patients.”
SÃ©zary syndrome’s incidence rate is between 0.3 and 2 cases per 100,000 people in the United States, annually. Patients have a 5-year survival rate of less than 30%.