TY - JOUR
T1 - Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia
AU - Kornblau, Steven M.
AU - Womble, Matthew
AU - Yi, Hua Qiu
AU - Jackson, C. Ellen
AU - Chen, Wenjing
AU - Konopleva, Marina
AU - Estey, Elihu H.
AU - Andreeff, Michael
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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 (PKCα, 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 PKCα, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKCα-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.
AB - 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 (PKCα, 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 PKCα, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKCα-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.
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U2 - 10.1182/blood-2006-02-003475
DO - 10.1182/blood-2006-02-003475
M3 - Article
C2 - 16763210
AN - SCOPUS:33749337234
SN - 0006-4971
VL - 108
SP - 2358
EP - 2365
JO - Blood
JF - Blood
IS - 7
ER -