Comment on Kornblau et al, page 2358

Kornblau and colleagues find that activation of multiple signal transduction pathways confers a poor clinical outcome in AML.

Leukemias are characterized by dysregulation of proliferation, differentiation, and the balance between cell life and death, with that balance shifted toward survival even in the face of major cellular stress. Such survival likely relates, at least in part, to activation of multiple interactive pathways rather than a single molecular lesion, with the result being a “cascade” of molecular activations that converge on central determinants of overall cellular survival.

Toward this end, the elegant studies of Kornblau and colleagues examine the net activities of 3 signal transduction pathways by measuring the magnitude of expression and activation status of PKCα, ERK2, and AKT in leukemic blasts from 188 adults with newly diagnosed acute myelogenous leukemia (AML). The work builds on the group's serial studies aimed at elucidating the relationships between activation status of selected signaling intermediaries, net function of BCL-2 family proteins, and overall clinical response.1,2  The intermediaries selected for study are very relevant, since each one represents a convergence point for distinctive pathways that modulate both gene transcription and mitochondrial processes and culminate in cell proliferation and survival (see figure).

The current study demonstrates that activation of 1 or more pathways are linked to a poor clinical prognosis in terms of achievement of complete remission, duration of remission, and overall survival. Indeed, in this large group of patients, there appears to be a “dose response,” with clinical outcome inversely related to the number of pathways activated. The additional finding of an “all-or-none” phenomenon, with activation of either none or all 3 pathways being the more common patterns, implies that at least for the “stimulated” populations, there may be an operative trigger or amplification mechanism in cells, such as contact between leukemic cells and bone marrow stroma.3  Not surprisingly, however, these findings are not universal, since certain molecular lesions, notably FLT3–internal tandem duplication (ITD), do not appear to be associated with activation of the particular pathways examined in this study.FIG1 

Prosurvival signaling pathways and their downstream targets. See the complete figure in the article beginning on page 2358.

Prosurvival signaling pathways and their downstream targets. See the complete figure in the article beginning on page 2358.

All of these findings are important because malignant cell survival depends on multiple interactive pathways that can be sustained by diverse intermediaries and, if 1 path is blocked, another can step up to maintain the cell's drive to survive. This compensatory ability suggests that the use of single “targeted” agents may well be suboptimal—a concept that, unfortunately, is all too well supported by clinical experience in all malignancies and has broad implications for the entire field of cancer therapeutics. We need to listen carefully to the authors' eloquent plea for a new paradigm in drug development, namely the testing of multiple investigational agents in ways that target complementary molecules and attack the malignant phenotype from multiple angles. ▪

1
Kornblau SM, Vu HT, Ruvolo P, et al. BAX and PKCα modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia.
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2
Milella M, Estrov Z, Kornblau SM, et al. Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia.
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3
Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M. Stromal cells prevent apoptosis of AML cells by upregulation of anti-apoptotic proteins.
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