title: Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Shuo-Chieh
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Loretta S
authors.initials: LS
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Kopp
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Montero
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Huiyun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Christodoulou
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Diederik
authors.initials: D
authors.lastname: van Bodegom
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jordy
authors.initials: J
authors.lastname: van der Zwet
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Layer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tivey
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Ryan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Samuel Y
authors.initials: SY
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Steensma
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Harris
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Emeline
authors.initials: E
authors.lastname: Mandon
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Rita
authors.initials: R
authors.lastname: Andraos
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Dölemeyer
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Sterker
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Zender
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Kuo
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. Electronic address: christoph.gaul@novartis.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: dweinstock@partners.org.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051379:Mice; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C000602006:CHZ868; D047428:Protein Kinase Inhibitors; D003907:Dexamethasone; C507924:JAK2 protein, human; D053614:Janus Kinase 2