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Jak2 inhibition deactivates Lyn kinase through the SET–PP2A–SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients

Oncogene volume 28, pages 1669–1681 (2009)Cite this article

Abstract

Chronic myelogenous leukemia (CML) patients treated with imatinib mesylate (IM) become drug resistant by mutations within the kinase domain of Bcr–Abl, and by other changes that cause progression to advanced stage (blast crisis) and increased expression of the Lyn tyrosine kinase, the regulation of which is not understood yet. In Bcr–Abl+ cells inhibition of Jak2, a downstream target of Bcr–Abl, by either Jak2 inhibitors or Jak2-specific short interfering RNA (siRNA) reduced the level of the SET protein, and increased PP2A Ser/Thr phosphatase and Shp1 tyrosine phosphatase activities, which led to decreased levels of activated Lyn. Activation of PP2A combined with Jak2 inhibition enhanced the reduction of activated Lyn kinase compared with Jak2 inhibition alone. In contrast, inhibition of either PP2A or Shp1 combined with Jak2 inhibition interfered with the loss of Lyn kinase activation more so than Jak2 inhibition alone, indicating the involvement of PP2A and Shp1 in the inactivation of the Lyn kinase caused by Jak2 inhibition. Inhibition of Jak2 induced apoptosis and reduced colony formation in IM-sensitive and -resistant Bcr–Abl mutant cell lines. Jak2 inhibition also induced apoptosis in CML cells from blast crisis patients but not in normal hematopoietic cells. These results indicate that Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET–PP2A–Shp1 pathway.

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Acknowledgements

This work was supported in part by grants CA49639 and CA093792 (RBA), CA095512 and DOD WB1XWH-07-1-0270 (DP), Leukemia Spore grant CA100632 (AKS), and Ladies Leukemia League (AKS). We thank Santhanam Ramasami, PhD in the Perrotti lab for his help in PP2A assay.

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Author notes

  1. J Hood

    Present address: 6Current address: Wintherix, LLC, San Diego, CA, USA.,

Authors and Affiliations

  1. Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A K Samanta, S N Chakraborty, Y Wang & R B Arlinghaus

  2. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Kantarjian

  3. Department of Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Sun

  4. TargeGen, Inc, San Diego, CA, USA

    J Hood

  5. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

    D Perrotti

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Correspondence to R B Arlinghaus.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Samanta, A., Chakraborty, S., Wang, Y. et al. Jak2 inhibition deactivates Lyn kinase through the SET–PP2A–SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients. Oncogene 28, 1669–1681 (2009). https://doi.org/10.1038/onc.2009.7

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