Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.
| Title | Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Wu, S-C., Li L. S., Kopp N., Montero J., Chapuy B., Yoda A., Christie A. L., Liu H., Christodoulou A., van Bodegom D., van der Zwet J., Layer J. V., Tivey T., Lane A. A., Ryan J. A., Ng S. Y., DeAngelo D. J., Stone R. M., Steensma D., Wadleigh M., Harris M., Mandon E., Ebel N., Andraos R., Romanet V., Dölemeyer A., Sterker D., Zender M., Rodig S. J., Murakami M., Hofmann F., Kuo F., Eck M. J., Silverman L. B., Sallan S. E., Letai A., Baffert F., Vangrevelinghe E., Radimerski T., Gaul C., & Weinstock D. M. |
| Journal | Cancer Cell |
| Volume | 28 |
| Issue | 1 |
| Pagination | 29-41 |
| Date Published | 2015 Jul 13 |
| ISSN | 1878-3686 |
| Keywords | Aminopyridines, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Benzimidazoles, Cell Line, Tumor, Cytoprotection, Dexamethasone, Drug Resistance, Neoplasm, Drug Synergism, Humans, Janus Kinase 2, Mice, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein Kinase Inhibitors, Signal Transduction, Xenograft Model Antitumor Assays |
| 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. |
| DOI | 10.1016/j.ccell.2015.06.005 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 26175414 |
| PubMed Central ID | PMC4505625 |
| Grant List | K08 CA181340 / CA / NCI NIH HHS / United States R01 CA151898 / CA / NCI NIH HHS / United States R01 CA172387 / CA / NCI NIH HHS / United States R01 GM110352 / GM / NIGMS NIH HHS / United States R01CA151898-01 / CA / NCI NIH HHS / United States T32 CA009172 / CA / NCI NIH HHS / United States T32 CA136432 / CA / NCI NIH HHS / United States T32 HL116324 / HL / NHLBI NIH HHS / United States T32 HL116324 / HL / NHLBI NIH HHS / United States |
