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Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10467-72. doi: 10.1073/pnas.1512396112. Epub 2015 Aug 3.

Ancient hot and cold genes and chemotherapy resistance emergence.

Author information

1
Princeton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544;
2
Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
3
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637;
4
Moffitt Cancer Center, Tampa, FL 33612;
5
Department of Bioengineering, University of California, Santa Cruz, CA 95064;
6
The Biodesign Institute, Arizona State University, Tempe, AZ 85287;
7
Beyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ 85287;
8
Department of Physics, Princeton University, Princeton, NJ 08544 austin@princeton.edu.

Abstract

We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.

KEYWORDS:

ancient genes; cancer; cold; emergence; hot

PMID:
26240372
PMCID:
PMC4547268
DOI:
10.1073/pnas.1512396112
[Indexed for MEDLINE]
Free PMC Article

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