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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2358-2365.
Prepublished online as a Blood First Edition Paper on June 8, 2006; DOI 10.1182/blood-2006-02-003475.
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NEOPLASIA
Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia
Steven M. Kornblau,
Matthew Womble,
Yi Hua Qiu,
C. Ellen Jackson,
Wenjing Chen,
Marina Konopleva,
Elihu H. Estey, and
Michael Andreeff
From the Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, and the Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX.
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 (PKC , 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 PKC, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKC-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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