Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

Shuo Chieh Wu, Loretta S. Li, Nadja Kopp, Joan Montero, Bjoern Chapuy, Akinori Yoda, Amanda L. Christie, Huiyun Liu, Alexandra Christodoulou, Diederik vanBodegom, Jordy vanderZwet, Jacob V. Layer, Trevor Tivey, Andrew A. Lane, Jeremy A. Ryan, Samuel Y. Ng, Daniel J. DeAngelo, Richard M. Stone, David Steensma, Martha WadleighMarian Harris, Emeline Mandon, Nicolas Ebel, Rita Andraos, Vincent Romanet, Arno Dölemeyer, Dario Sterker, Michael Zender, Scott J. Rodig, Masato Murakami, Francesco Hofmann, Frank Kuo, Michael J. Eck, Lewis B. Silverman, Stephen E. Sallan, Anthony Letai, Fabienne Baffert, Eric Vangrevelinghe, Thomas Radimerski, Christoph Gaul*, David M. Weinstock

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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 invivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.

Original languageEnglish (US)
Pages (from-to)29-41
Number of pages13
JournalCancer Cell
Volume28
Issue number1
DOIs
StatePublished - Jul 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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