title: Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia.
abstract: Deregulation of signal transduction pathways (STPs) may promote leukemogenesis by conferring cell proliferation and survival advantages in acute myelogenous leukemia (AML). Several agents targeting STPs are under development; however, redundancy and cross-talk between STPs could activate multiple downstream effectors and this could negate the effect of single-target inhibition. The frequency of concurrent activation of multiple STPs in AML and the prognostic relevance of STP activation in AML are unknown. STP protein expression (PKCalpha, ERK2, pERK2, AKT, and pAKT) was measured by Western blot in samples from 188 patients with newly diagnosed, untreated AML. In univariate and multivariate analysis high levels of PKCalpha, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKCalpha-ERK2&pERK2-pAKT. Survival progressively decreased as the number of activated pathways increased. Patients were more likely to have none or all 3 pathways activated than was predicted based on the frequency of individual pathway activation, strongly suggesting that cross-activation occurred. Simultaneous activation of multiple STPs is common in AML and has a progressively worse adverse effect on prognosis. It is thus likely that only combinations of agents that target the multiply activated STPs will be beneficial for patients with AML.
authors.affiliation: Section of Molecular Hematology and Therapy, Unit 448, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. skornbla@mdanderson.org
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Matthew
authors.initials: M
authors.lastname: Womble
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.forename: C Ellen
authors.initials: CE
authors.lastname: Jackson
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chen
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000368:Aged; D004789:Enzyme Activation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D011379:Prognosis; D011446:Prospective Studies; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013997:Time Factors; D016896:Treatment Outcome