Journal
CANCER CELL
Volume 28, Issue 1, Pages 29-41Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.06.005
Keywords
-
Categories
Funding
- Dana-Farber/Novartis Drug Discovery Program
- National Cancer Institute [R01 CA151898-01, T32 CA136432]
- Novartis
- National Heart, Lung, and Blood Institute [T32 HL116324]
Ask authors/readers for more resources
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 hyperphos-phorylation 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available