JAK-STAT signaling keeps leukemia cells alive

Large granular lymphocyte (LGL) leukemia is characterized by the clonal expansion of a T-cell population sharing many similarities with antigen-activated cytotoxic T lymphocytes (CTLs). Unlike normal CTLs, which are readily targeted for destruction by Fas ligand (FasL) binding to the Fas receptor, leukemic LGLs resist Fas-mediated apoptosis. Here, Epling-Burnette and co-workers present data on abnormalities underlying LGL leukemia. Because constitutive activation of STAT transcription factors had been shown to promote resistance to apoptosis in other systems, these authors have assessed the role of STAT proteins in LGL leukemia. They show here that leukemic LGLs from all patients studied showed constitutive activation of STAT3 and/or STAT1, which are normally held latent in the cytoplasm until they are activated by tyrosine kinases of the JAK family.

Epling-Burnette et al. show that AG-490, an inhibitor of JAKs, blocks STAT3 function and promotes apoptosis of LGL leukemic cells. While prior studies of other types of leukemia and solid tumors had suggested STAT activation might promote resistance to apoptosis via induction of the Bcl-X L protein, the authors found no evidence that Bcl-X L was highly expressed in leukemic LGLs; rather, the authors found increased expression of Mcl-1, an anti-apoptotic factor in the Bcl-2 family whose expression is regulated by STAT3. The work reinforces the view that chemotherapeutic agents inhibiting the JAK-STAT pathway might prove of considerable utility in treating LGL leukemia and perhaps other neoplasms.


Contact: john ashkenas
Journal of Clinical Investigation

Page: 1

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