Genetically identical cells, even within the same tissue, are often observed to have different levels of gene expression. So what effect does it have on the individual? Once seen as random ‘noise’, heterogeneity in gene expression is increasingly seen as having potentially profound biological and medical consequences. Now, a study by Alfonso Valencia and colleagues from the Spanish National Cancer Research Centre, Spain, published in Genome Medicine, has found a relationship between variation in gene expression and disease aggressiveness in chronic lymphocytic leukaemia (CLL).
CLL is a slowly developing cancer of the lymphocytes, with two major subtypes defined by the mutational status of the immunoglobulin heavy chain variable region (IgVH); mutated C-LL (M-CLL), where patients show a larger number of mutations in the IgVH and unmutated CLL (U-CLL), with patients showing fewer mutations in the IgVH. Studies have found that U-CLL is clearly associated with a more progressive disease and has a significant impact on survival.
The authors analysed gene expression data of two large cohorts of CLL patients using previously-published microarray datasets. By applying a range of measures and statistical tests, they found a strong relationship between disease subtype and gene expression variability; the more aggressive type, U-CLL, had far greater variation in gene expression. They were even able to classify patients into disease subtypes based on their gene expression signatures. In contrast, the levels of gene expression in U-CLL and M-CLL patients showed very little difference.
Valencia and colleagues also explored specific functional classes of genes most affected by this differential variability, finding significantly enriched genes in the U-CLL subtype for inter-cellular communication and signal transduction – basic components of leukaemia development and CLL progression. Further important functions showing increased variability in U-CLL patients were related to proliferation, growth, development, and programmed cell-death, reinforcing the possible link between increased heterogeneity in gene expression and clinical subtypes.
This study reveals that gene expression heterogeneity, rather than general levels of expression, is able to discriminate between the two major CLL subtypes. The results also suggest that gene expression heterogeneity may play a role in the speed of progression of U-CLL and its resistance to therapy. The outcomes seem to concur with suggestions that using drugs that reduce cell-to-cell variability alongside other drug therapies may be a promising strategy for future therapies.
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