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January 24, 2011

Genetic diversity in leukemia cells

by Chris Kamel

Although tumours are typically thought of as a single entity, the cells that make up a tumour are genetically diverse. The traditional view of cancer progression -- in which a tumour arises from a single cell after accumulated mutations -- suggests that tumour cells, while genetically diverse due to selective pressures and other evolutionary forces, are all linearly related. Similarly, in the cancer stem cell model, tumour growth is driven by an underlying stem cell population and tumour cells would be genetically related. Work published this week in Nature challenges assumptions about the relationships between cells within a single tumour.

The work, done by Dr. John Dick's group at the Ontario Cancer Institute, used a leukemia model and a combination of tumour transplant and genetic profiling and found that cells taken from patients with acute lymphoblastic leukemia are actually derived from multiple distinct families. Tracing the the ancestry of these cells, they found that rather than a linear evolutionary succession, the profiles indicated a more complex branching relationship of various sub-families. Furthermore, they found that mutations in certain gene families, such as the cell cycle regulators CDKN2A and CDKN2B, were associated with more aggressive tumours when transplanted in animal models and poorer prognosis when found in patients.

Importantly, the fact that the cells come from distinct families may explain some of the difficulties in treating cancer. Treatments that eliminate one genetic family may leave behind other distinct subtypes that can continue to grow and repopulate the tumour. In the cancer stem cell model, underlying stem cells are thought to drive tumour growth and eliminating these cells is a goal of therapy. Given these new results that indicate a number of genetically distinct sub-populations that make up a tumour, broader approaches that target multiple of these families could be necessary for complete cancer eradication.

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Some of these gene families dominate, making it appear that the leukemia cells have only one set of genetic abnormalities, while other families are very rare, explaining why he had never seen before.

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