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Clinical Topics

JAK Enzymes Can Treat Leukemia, Lymphoma

by U.S. Medicine

April 23, 2019

NASHVILLE, TN—Precision oncology prescribes the use of molecularly-targeted therapy directed by identification of genomic alterations. A new study suggested the approach is particularly applicable to neoplasms that are resistant to standard cytotoxic chemotherapy, such as T-cell leukemias and lymphomas.

A study team led by Vanderbilt University researchers and including participation from the Roudebush VAMC in Indianapolis tested the feasibility of targeted next-generation sequencing in profiles of diverse T-cell neoplasms. Researchers also focused on the therapeutic utility of targeting activated JAK1 and JAK3 in an index case.

The study was published in JCO Precision Oncology.1

Using Foundation One and Foundation One Heme assays, investigators performed genomic profiling on 91 consecutive T-cell neoplasms for alterations in 405 genes. They found that one-third of the samples had genomic aberrations in the JAK-STAT pathway, which, in most cases, was composed of JAK1 and JAK3 gain-of-function mutations.

The study also presents an index case of a patient with T-PLL with a clonal JAK1 V658F mutation that responded to ruxolitinib therapy. “After relapse developed, an expanded clone that harbored mutant JAK3 M511I and downregulation of the phosphatase, CD45, was identified. We demonstrate that the JAK missense mutations were activating, caused pathway hyperactivation and conferred cytokine hypersensitivity,” the authors noted.

“These results underscore the utility of profiling occurrences of resistance to standard regimens and support JAK enzymes as rational therapeutic targets for T-cell leukemias and lymphomas,” the researchers concluded.

Greenplate A, Wang K, Tripathi RM, Palma N, Ali SM, Stephens PJ, Miller VA, Shyr Y, Guo Y, Reddy NM, Kozhaya L, Unutmaz D, Chen X, Irish JM, Davé UP. Genomic Profiling of T-Cell Neoplasms Reveals Frequent JAK1 and JAK3 Mutations With Clonal Evasion From Targeted Therapies. JCO Precis Oncol. 2018;2018. doi 10.1200/PO.17.00019. Epub 2018 Feb 13. PubMed PMID: 30079384; PubMed Central PMCID: PMC6072266.



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