1. ¹Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴TargeGen, Inc., San Diego, CA, USA
5. ⁵Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

Correspondence: Professor RB Arlinghaus, Department of Molecular Pathology, The University of Texas, UTMD Anderson Cancer Center, 7435 Fannin Street, Unit 951, Houston, TX 77054, USA. E-mail: rarlingh@mdanderson.org

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

Received 26 September 2008; Revised 17 December 2008; Accepted 18 December 2008; Published online 23 February 2009.

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.