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Type II JAK2 inhibition in B-cell acute lymphoblastic leukemia

Gaul, Christoph and Radimerski, Thomas and Vangrevelinghe, Eric and Baffert, Fabienne and Hofmann, Francesco and Murakami, Masato and Sterker, Dario and Doelemeyer, Arno and Romanet, Vincent and Andraos-Rey, Rita and Ebel, Nicolas and Mandon, Emeline and Zender, Michael and Weinstock, David M. and Letai, Anthony and Sallan, Stephen E. and Silverman, Lewis and Eck, Michael J. and Rodig, Scott J. and Wu, Shuo-Chieh and Li, Loretta S. and Kopp, Nadja and Montero, Joan and Chapuy, Bjoern and Christie, Amanda L. and Liu, Huiyun and Christodoulou, Alexandra and van Bodegom, Diederik and Tivey, Trevor and Lane, Andrew A. and Ryan, Jeremy A. and Yoda, Akinori and DeAngelo, Daniel and Stone, Richard M. and Steensma, David and Wadleigh, Martha and Harris, Marian (2015) Type II JAK2 inhibition in B-cell acute lymphoblastic leukemia. Cancer Cell, 28 (1). pp. 29-41.

Abstract

A variety of cancers depend on JAK2 signaling, including the high-risk subset of B-cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce JAK2 hyperphosphorylation in these leukemias and have limited activity. To overcome this, we developed the type II inhibitor NVP-CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with primary human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis of CRLF2-rearranged human B-ALL cells and improved survival compared to CHZ868 alone. Together, these data provide the foundation for trials of type II JAK2 inhibition in patients with CRLF2-rearranged B-ALL and other JAK2-dependent disorders.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23791

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