Editors' ChoiceCancer

Mirror, Mirror, on the Wall, Which Way Will the Balance Fall?

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Science Translational Medicine  11 Apr 2012:
Vol. 4, Issue 129, pp. 129ec63
DOI: 10.1126/scitranslmed.3004093

Hematopoiesis—the formation of new blood cells—is a precisely balanced process: If tipped in the wrong direction, cancers such as leukemia or lymphoma can result. Small, nonprotein-coding microRNAs (miRNAs) play a key role during hematopoiesis through posttranscriptional regulation of gene expression. The miR-17-92 locus, which produces a single transcript that is processed to form six mature miRNAs, is frequently overexpressed in human cancers. The oncogenic potential of this miRNA cluster has been suggested by in vitro studies but not adequately tested in vivo.

Li and colleagues explored the role of each member of miR-17-92 in leukemia by overexpressing the entire miR-17-92 cluster or its individual miRNAs, including miR-92a, miR-17, and miR-19a, in newborn mice via retroviral vectors. Mice that overexpressed the entire cluster had enlarged, abnormally organized spleens—an organ that contributes to hematopoiesis—but displayed no other evidence of disease. Experiments with isolated splenocytes revealed an increase in multipotent hematopoietic progenitor cells that could differentiate into lymphoid and myeloid cells. In contrast, mice that overexpressed miR-92a alone developed a form of leukemia (involving proliferation of erythroid precursor cells) through up-regulation of genes involved in this process such as c-Myc, but this leukemia was suppressed by co-overexpression of miR-17, which down-regulated genes involved in erythroid proliferation. Additionally, overexpression of miR-19a on its own caused B cell expansion but not B cell lymphoma. Furthermore, the researchers found that in both mouse and human leukemia cell lines, p53 inactivation contributed to an imbalanced expression of the miR-17-92 cluster, which is characterized by elevated levels of oncogenic miR-92a and miR-19a and depressed levels of tumor-suppressive miR-17. This altered balance was also observed in a clinically aggressive form of B cell chronic lymphocytic leukemia that lacks p53 expression.

These findings underscore the importance of a balanced regulation of biological processes. Tipping the balance toward leukemia can be achieved by over- or under-expression of not only proteins but also miRNAs. This study is important because it provides new molecular targets for diagnosing and treating cancers that harbor miR-17-92 gene amplification.

Y. Li et al., The miR-17-92 cluster expands multipotent hematopoietic progenitors while imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice. Blood 26 March 2012 (10.1182/blood-2011-09-378687). [Abstract]

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