Type II JAK2 inhibition in B-cell acute lymphoblastic leukemia
- Gaul, Christoph
- Radimerski, Thomas
- Vangrevelinghe, Eric
- Baffert, Fabienne
- Hofmann, Francesco
- Murakami, Masato
- Sterker, Dario
- Doelemeyer, Arno
- Romanet, Vincent
- Andraos-Rey, Rita
- Ebel, Nicolas
- Mandon, Emeline
- Zender, Michael
- Weinstock, David M.
- Letai, Anthony
- Sallan, Stephen E.
- Silverman, Lewis
- Eck, Michael J.
- Rodig, Scott J.
- Wu, Shuo-Chieh
- Li, Loretta S.
- Kopp, Nadja
- Montero, Joan
- Chapuy, Bjoern
- Christie, Amanda L.
- Liu, Huiyun
- Christodoulou, Alexandra
- van Bodegom, Diederik
- Tivey, Trevor
- Lane, Andrew A.
- Ryan, Jeremy A.
- Yoda, Akinori
- DeAngelo, Daniel
- Stone, Richard M.
- Steensma, David
- Wadleigh, Martha
- Harris, Marian
DOIAbstract
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 JAK2 hyperphosphorylation in these leukemias and have limited activity. To overcome this, we developed the type II inhibitor NVP-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 primary human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis of CRLF2-rearranged human B-ALL cells and improved survival compared to CHZ868 alone. Together, these data provide the foundation for trials of t...
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