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

Cancer Cell
Authors
Keywords
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.

Year of Publication
2015
Journal
Cancer Cell
Volume
28
Issue
1
Pages
29-41
Date Published
2015 Jul 13
ISSN
1878-3686
URL
DOI
10.1016/j.ccell.2015.06.005
PubMed ID
26175414
PubMed Central ID
PMC4505625
Links
Grant list
T32 CA136432 / CA / NCI NIH HHS / United States
R01 CA151898 / CA / NCI NIH HHS / United States
T32 HL116324 / HL / NHLBI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
K08 CA181340 / CA / NCI NIH HHS / United States
R01CA151898-01 / CA / NCI NIH HHS / United States
R01 GM110352 / GM / NIGMS NIH HHS / United States
R01 CA172387 / CA / NCI NIH HHS / United States