Leukemia

Leukemia does not live by 1 lesion alone

Judith E. Karp
SIDNEY KIMMEL CANCER CENTER AT JOHNS HOPKINS

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.

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. 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.

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.

Blood, 1 October 2006, Vol. 108, No. 7, pp. 2133-2134.