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Departments of 1 Molecular Pathology and 2 Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Ralph B. Arlinghaus, Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 712-792-8995; Fax: 713-794-1395; E-mail: rarlingh{at}mdanderson.org.
The Bcr-Abl tyrosine kinase is the causative factor in most chronic myelogenous leukemia (CML) patients. We have shown that Bcr-Abl is associated with a cluster of signaling proteins, including Janus kinase (Jak) 2, growth factor receptor binding protein 2–associated binder (Gab) 2, Akt, and glycogen synthase kinase (GSK)-3ß. Treatment of CML cell lines and mouse Bcr-Abl+ 32D cells with either Jak2 short interfering RNA or Jak2 kinase inhibitor AG490 inhibited pTyr Gab2 and pSer Akt formation, inhibited the activation of nuclear factor-
B, and caused the activation of GSK-3ß, leading to the reduction of c-Myc. Importantly, BaF3 cells expressing T315I and E255K imatinib-resistant mutants of Bcr-Abl underwent apoptosis on exposure to AG490 yet were resistant to imatinib. Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells. These results identify Jak2 as a potentially important therapeutic target for CML. (Cancer Res 2006; 66(13): 6468-72)
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