JAK3 Mutations Identified in Natural Killer/T-Cell Lymphoma

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(ChemotherapyAdvisor) – Activating mutations of Janus kinase 3 (JAK3) have been identified that may play a significant role in the pathogenesis of natural killer/T-cell lymphoma (NKTCL), opening the door to development of treatment with Janus kinase inhibitors, a study published in Cancer Discovery online June 15 has found.

These findings are bittersweet: in 1999, lead investigator Bin Tean Teh, MD, PhD, began working with Han-Mo Koo at the Van Andel Institute, Grand Rapids, MI. However, Dr. Koo passed away from NKTCL—the only case ever recorded in Grand Rapids—in 2004, at the age of 40 years. Dr. Teh, now director of the National Cancer Center Singapore-Van Andel Research Institute Translational Research Laboratory and professor at the Duke-NUS Graduate Medical School in Singapore, promised him he would dedicate his efforts toward finding the genetic basis of the disease.

The investigators conducted whole-exome sequencing and identified JAK3 somatic-activating mutations A572V and A573V in 2 of 4 patients with NKTCL. Sanger sequencing and high-resolution melt (HRM) analysis further validated prevalence of JAK3mutations in an additional 61 cases; 23 of 65 (35.4%) cases harbored JAK3mutations.

“Functional characterization of the JAK3mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth,” they wrote. “Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis.”

Dr. Teh noted they are currently proposing testing JAK inhibitors as a treatment for NKTCL with JAK3 mutations, as these results suggest targeting the deregulated JAK/STAT pathway “represents a promising therapy for patients with NKTCL.”


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