@article{866c9d2dd67940039d607a2f07e4e56e,
title = "Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia",
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.",
author = "Wu, {Shuo Chieh} and Li, {Loretta S.} and Nadja Kopp and Joan Montero and Bjoern Chapuy and Akinori Yoda and Christie, {Amanda L.} and Huiyun Liu and Alexandra Christodoulou and Diederik vanBodegom and Jordy vanderZwet and Layer, {Jacob V.} and Trevor Tivey and Lane, {Andrew A.} and Ryan, {Jeremy A.} and Ng, {Samuel Y.} and DeAngelo, {Daniel J.} and Stone, {Richard M.} and David Steensma and Martha Wadleigh and Marian Harris and Emeline Mandon and Nicolas Ebel and Rita Andraos and Vincent Romanet and Arno D{\"o}lemeyer and Dario Sterker and Michael Zender and Rodig, {Scott J.} and Masato Murakami and Francesco Hofmann and Frank Kuo and Eck, {Michael J.} and Silverman, {Lewis B.} and Sallan, {Stephen E.} and Anthony Letai and Fabienne Baffert and Eric Vangrevelinghe and Thomas Radimerski and Christoph Gaul and Weinstock, {David M.}",
note = "Funding Information: We thank Oliver Weigert for technical advice and previous constructs; Ilene Galinsky, Samia Ahmed, and Katharine Majewski for sample procurement; and Shai Izraeli for thoughtful comments. We thank all the patients who contributed invaluable samples. We thank Aaron Thorner, Paul Van Hummelen, Matthew Ducar, and Bruce Wollison of the DFCI Center for Cancer Genome Discovery for assistance with genomic characterization. We thank Jerome Tamburini, Michael McKeown, and Elizabeth Townsend for their technical advice. This work was supported by the Dana-Farber/Novartis Drug Discovery Program (D.M.W.), the National Cancer Institute (R01 CA151898-01 to D.M.W. and T32 CA136432 to L.S.L.), and the National Heart, Lung, and Blood Institute (T32 HL116324 to L.S.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, National Heart, Lung, and Blood Institute, or the NIH. E.M., N.E., R.A., V.R., A.D., D.S., M.Z., M.M., F.H., F.B., E.V., T.R., and C.G. are or have been employees of Novartis Pharma AG. D.M.W. and M.J.E. received research funding from Novartis. ",
year = "2015",
month = jul,
day = "13",
doi = "10.1016/j.ccell.2015.06.005",
language = "English (US)",
volume = "28",
pages = "29--41",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}