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

• Published in: Oncogene Vol. 28; no. 14; pp. 1669 - 1681
• Main Authors: Samanta, A K, Chakraborty, S N, Wang, Y, Kantarjian, H, Sun, X, Hood, J, Perrotti, D, Arlinghaus, R B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.04.2009; Nature Publishing Group
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis - drug effects; BCR protein; Benzamides; Biological and medical sciences; Blast crisis; Care and treatment; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromosomal Proteins, Non-Histone - physiology; Chronic myeloid leukemia; Cyclohexanes - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Histone Chaperones; Human Genetics; Humans; Imatinib; Imatinib Mesylate; Internal Medicine; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - physiology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Myeloid leukemia; Oncology; original-article; Phosphatase; Phosphorylation; Piperazines - pharmacology; Protein kinases; Protein Phosphatase 2 - physiology; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - physiology; Protein-tyrosine kinase; Protein-tyrosine-phosphatase; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; SHP-1 protein; siRNA; src-Family Kinases - metabolism; Transcription Factors - physiology; Tyrphostins - pharmacology; United States; Lyn; BCR–ABL; drug-resistance; PP2A; SET; Jak2; Human; drug- resistance; Treatment resistance; Enzyme; Transferases; BCR-ABL; Chronic myelogenous leukemia; Malignant hemopathy; Carcinogenesis; Myeloproliferative syndrome; Kinase; Inhibition; Protein-tyrosine kinase; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.7

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.