| Literature DB >> 26175414 |
Shuo-Chieh Wu1, Loretta S Li2, Nadja Kopp1, Joan Montero1, Bjoern Chapuy1, Akinori Yoda1, Amanda L Christie1, Huiyun Liu1, Alexandra Christodoulou1, Diederik van Bodegom1, Jordy van der Zwet1, Jacob V Layer1, Trevor Tivey1, Andrew A Lane1, Jeremy A Ryan1, Samuel Y Ng1, Daniel J DeAngelo1, Richard M Stone1, David Steensma1, Martha Wadleigh1, Marian Harris3, Emeline Mandon4, Nicolas Ebel4, Rita Andraos4, Vincent Romanet4, Arno Dölemeyer4, Dario Sterker4, Michael Zender4, Scott J Rodig5, Masato Murakami4, Francesco Hofmann4, Frank Kuo5, Michael J Eck6, Lewis B Silverman3, Stephen E Sallan3, Anthony Letai1, Fabienne Baffert4, Eric Vangrevelinghe4, Thomas Radimerski4, Christoph Gaul7, David M Weinstock8.
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 paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor 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 human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.Entities:
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Year: 2015 PMID： 26175414 PMCID： PMC4505625 DOI： 10.1016/j.ccell.2015.06.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743