title: Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements.
abstract: JAK2 fusion genes are rare but recurrent abnormalities associated with diverse, clinically heterogeneous hematologic malignancies. Here we assess the JAK1/2 inhibitor ruxolitinib as therapy for patients with JAK2-rearrangement associated myeloproliferative neoplasms (MPN). Ruxolitinib-treated Ba/F3 cells transformed to IL3 independence by ETV6-JAK2 showed reduced proliferation and survival (IC(50) = 370 nM) compared with KG1A or Ba/F3 cells transformed by BCR-ABL1, SPBN1-FLT3 and ZMYM2-FGFR1 (IC(50) > 10 μM for all). Inhibition was associated with reduced phosphorylation of ETV6-JAK2, ERK, STAT5 and AKT. Primary cell growth from 2 patients with JAK2 rearrangement and one patient with JAK2 amplification was assessed in methylcellulose assays. Reduced colony growth was seen for all patients in ruxolitinib-treated cultures compared with healthy controls (n=7). Fluorescence in situ hybridization showed reduced growth of JAK2-rearrangement positive colonies compared to JAK2-rearrangement negative colonies. Our data, therefore, provide evidence that ruxolitinib is a promising therapy for treatment of patients with JAK2 fusion genes.
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Catherine
authors.initials: C
authors.lastname: Bryant
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Vera
authors.initials: V
authors.lastname: Grossmann
authors.forename: Juliana
authors.initials: J
authors.lastname: Schwaab
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D009570:Nitriles; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D053614:Janus Kinase 2; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C540383:ruxolitinib