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Cancer Cell. 2015 Jul 13;28(1):29-41. doi: 10.1016/j.ccell.2015.06.005.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
5
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7
Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. Electronic address: christoph.gaul@novartis.com.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: dweinstock@partners.org.

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.

PMID:
26175414
PMCID:
PMC4505625
DOI:
10.1016/j.ccell.2015.06.005
[Indexed for MEDLINE]
Free PMC Article

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