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J. Biol. Chem., Vol. 282, Issue 6, 3428-3432, February 9, 2007

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Erlotinib Effectively Inhibits JAK2^V617F Activity and Polycythemia Vera Cell Growth^*

Zhe Li¹, Mingjiang Xu^¶1, Shu Xing, Wanting Tina Ho, Takefumi Ishii^¶, Qingshan Li, Xueqi Fu, and Zhizhuang Joe Zhao²

From the Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, the Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun 130023, China, the ^¶Section of Hematology/Oncology, University of Illinois at Chicago Cancer Center, University of Illinois College of Medicine, Chicago, Illinois 60612

JAK2^V617F, a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The JAK2 mutant displays a much increased kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. This study shows that the anti-cancer drug erlotinib (Tarceva^TM) is a potent inhibitor of JAK2^V617F activity. In vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppresses the growth and expansion of PV hematopoietic progenitor cells while having little effect on normal cells. Furthermore, JAK2^V617F-positive cells from PV patients show greater susceptibility to the inhibitor than their negative counterparts. Similar inhibitory effects were found with the JAK2^V617F-positive human erythroleukemia HEL cell line. These data suggest that erlotinib may be used for treatment of JAK2^V617F-positive PV and other myeloproliferative disorders.

Received for publication, October 23, 2006 , and in revised form, December 15, 2006.

^* This work was supported by Grants HL076309 and HL079441 from the National Institutes of Health (to Z. J. Z.) and Grant 30470391 from the National Natural Science Foundation of China (to X. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 405-271-9344; E-mail: joe-zhao{at}ouhsc.edu.

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