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Recurrent Mutations in Epigenetic Modifiers and JAK-STAT Pathway Seen in Sezary Syndrome, a Rare, Aggressive Leukemia; Results Highlight Genetic Vulnerabilities That Can Be Targeted in Precision Medicine Therapies

Sezary syndrome (SS), an aggressive leukemia of mature T cells, is more complicated at a molecular level than ever suspected, according to investigators from the Perelman School of Medicine at the University of Pennsylvania, and from collaborating institutions. With a poor prognosis and limited options for targeted therapies, fighting SS needs new treatment approaches. The team's results uncover a previously unknown, complex genomic landscape of this cancer, which can be used to design new personalized drug regimens for SS patients based on their unique genetic makeups. SS is a rare condition. Its incidence is estimated to be about 0.3-2 cases per 100,000 in the United States each year, and those patients have a five-year survival rate of less than 30 percent. Penn Medicine has one of the largest referral clinics for treatment of SS patients in the country. Taking a thorough approach to find SS mutations, senior authors Megan S. Lim, M.D., Ph.D., a Professor of Pathology and Laboratory Medicine, and Kojo Elenitoba-Johnson, M.D., the Peter C. Nowell, M.D. Professor and Director of the Center for Personalized Diagnostics, were not disappointed. "We basically found chromosomal chaos in all of our samples," Dr. Elenitoba-Johnson said. The research results were published online on September 29, 2015 in an open-access article in Nature Communications. The title of the article is “Genomic Analyses Reveal Recurrent Mutations in Epigenetic Modifiers and the JAK–STAT Pathway in Sézary Syndrome.” The team integrated three complementary gene sequencing approaches to look for mutations in tumor cells from SS patients: whole-genome sequencing in six subjects, exome sequencing of all protein-coding regions in 66 subjects, and comparing variation in the number of copies of all genes across the genome in 80 subjects. "We did not expect the degree of genetic complexity that we found in our study," Dr. Elenitoba-Johnson added.

They identified previously unknown recurrent loss-of-function mutations that target genes that regulate epigenetic pathways, i.e., genes whose protein products act on how tightly or loosely chromosome regions are wound and thus how accessible those chromosomal regions are for genes to be expressed.

One of these targeted epigenetic regulatory genes is called ARID1A, and the researchers found that loss-of-function mutations and/or deletions in ARID1A occurred in over 40 percent of the SS genomes studied.

They also identified "gain-of-function" mutations in PLCG1, JAK1, JAK3, STAT3, and STAT5B. In preliminary drug-mutation matching studies, they found that JAK1-mutated SS cells were sensitive to JAK inhibitors, drugs that are currently approved for treatment of other hematologic cancers such as polycythemia vera and myelofibrosis.

"With knowledge like this, we can design clinical trials using JAK inhibitors for SS patients based on their JAK mutations," said Dr. Elenitoba-Johnson. "But this is just the start. These results highlight the genetic vulnerabilities that we can use in designing precision medicine therapies."

The Penn team, in collaboration with Alain Rook, M.D., Director of the Cutaneous T-cell Lymphoma Program and a Professor of Dermatology, aims to develop a molecular taxonomy for mutations in SS patients.

With the state-of-the-art DNA sequencing technology used in this study, they will be able to pinpoint the exact mistake in each patient's SS-related genes. From this, they will also be able to identify distinct subsets of the disease to stratify patients for precision therapy based on their unique mutations and the inhibitors available for those mutations.

Additional co-authors of the Nature Communications article are Mark J. Kiel, Anagh A. Sahasrabuddhe, Delphine C.M. Rolland, Thirunavukkarasu Velusamy, Fuzon Chung, Matthew Schaller, Nathanael G. Bailey, Bryan L. Betz, Roberto N. Miranda, Pierluigi Porcu, John C. Byrd, L. Jeffrey Medeiros, Steven L. Kunkel, and David W. Bahler.

This work was partly supported by the National Cancer Institute and the Department of Pathology at the University of Michigan.

[Press release] [Nature Communications article]