Damage control by hypoxia-inhibited AK.

design of additional anti-LSC agents. Most interestingly, these compounds have been identified using a gene-expression signature derived from primitive AML CD34 ϩ cells to search through a broad spectrum of expression data obtained from several treatments performed on different nonhematopoi-etic cell types. This raises 2 important points. First, there may be no need to look at specific cancer stem cell (CSC) expression profiles to identify agents that specifically target CSCs if the initial search criteria are based on CSC drug-gene response, and second, different types of cancer might share common tumor-specific mechanisms of growth and survival that can be exploited to design new, effective anticancer therapies. Of course, other important issues remain: although these compounds effectively eradicate AML at the bulk, progenitor, and SL-IC level in vitro, there is no evidence of an effect in vivo, which is a likely clinical approach to avoid complex ex vivo culture treatment. In addition, these data need to be interpreted with caution. Celastrol and HNE clearly inhibit the leukemic-initiating cell function, but the effectiveness of these compounds on established leukemia versus leukemia initiation detected in surrogate in vivo SL-IC models still needs to be determined. Moreover, the relevance of the SL-IC assay in the detection of cells that have clinical significance for AML disease progression in patients still needs to be clarified, especially because there may be varying subclasses of SL-ICs that are detectable in different murine recipients and delivery methods in human-mouse xenograft models. Finally , the pharmacological use of the agents identified in the present study is difficult, due to the high concentration necessary to achieve SL-IC–specific eradication; analogs with better pharmacological properties or combinations that may lower the effective dose per agent need to be explored. Altogether, Hassane and colleagues make an important step forward in the discovery of new compounds that may effectively target putative LSCs while sparing normal HSCs. Perhaps more importantly, they provide a powerful experimental strategy for discovering new drugs and targets by using publicly available data. These findings underscore the importance of open-access data and the need for annotation standards and consistent mi-croarray normalization to enhance the utility of the underestimated knowledge contained in databases like Gene Expression Omnibus for LSCs, but also for other solid tumors that seemingly contain CSCs. 3 Conflict-of-interest disclosure: The authors declare no competing financial interests. ■ REFERENCES 1. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as …