title: Expression of p-JAK2 predicts clinical outcome and is a potential molecular target of acute myelogenous leukemia.
abstract: Our study determined if Janus kinase 2 (JAK2) was activated in acute myelogenous leukemia (AML; n = 77, excluding acute promyelocytic leukemia) by immunohistochemistry (IHC) using a phosphor-specific antibody against JAK2. p-JAK2 was detectable in all cases, although its levels varied between patient samples (high levels, n = 31; low levels, n = 46). The quantification of levels of p-JAK2 by IHC was well correlated with that assessed by Western blot analyses and fluorescence-activated cell sorting (FACS). Levels of p-JAK2 were directly correlated with high white blood cell count (52.3 × 10(3) /L in patients with high p-JAK2 vs. 28.3 × 10(3) /L in patients with low p-JAK2, p < 0.01) and were inversely correlated with complete remission rates (45% in patients with high p-JAK2 vs. 78% in patients with low p-JAK2, p < 0.003). In addition, multivariate analysis confirmed that high levels of p-JAK2 remained a significant factor for overall survival (hazard ratio = 2.213; 95% confidence interval, 1.212-4.041, p = 0.023). Moreover, we found that AZ960, a novel and specific inhibitor of the JAK2 kinase, potently inhibited the clonogenic growth and induced apoptosis of freshly isolated AML cells from patients in association with cleavage of caspase 3 and downregulation of anti-apoptotic Bcl-xL proteins. Taken together, JAK2 may be a promising molecular target for treatment of AML.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. ikezoet@kochi-u.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kojima
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Asako
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Mayuka
authors.initials: M
authors.lastname: Isaka
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow / Q000737:chemistry; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology
chemical_list: C534391:5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile; D000631:Aminopyridines; D018952:Antigens, CD34; D011720:Pyrazoles; D053614:Janus Kinase 2