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barbara
08-29-2012, 12:28 PM
Biotechiques
08/29/2012 Ashley Yeager

By isolating individual blood stem cells and sequencing their genomes, Stanford researchers have tracked the series of mutations that transforms blood stem cells into cancerous entities.

Blood cancers, and possibly all cancers, form when stem cells accrue rare genetic mutations, a new study shows. The discovery overturns the traditional view that blood cancers can originate from any blood cell and could help to prevent relapses in leukemia patients.

To identify the origins of leukemia, the team—led by Stanford University researchers—used next-generation sequencing and other methods to isolate the rare, pre-cancerous, blood stem cells found in six individuals with acute myeloid leukemia. The scientists then compared the genetic sequences from the pre-cancerous blood stem cells to the same regions from the patients’ leukemia-plagued stem cells. As a result, the analysis revealed the exact order of rare mutations that blood stem cells accrued to become cancerous. The results appear online August 29 in Science Translational Medicine (1).

“I’m surprised that we identified the clonal hierarchy that led to leukemia in five of the six cases. I didn’t think we’d find that amount of evidence of pre-leukemia stem cells,” said Stanford hematologist Ravi Majeti, co-lead author of the study.

For several decades, scientists have proposed that cancer stem cells, and particularly leukemia stem cells, lead to the disease. In 2005, Stanford pathologist Irving Weissman added a twist to the idea; he proposed that normal blood stem cells become cancerous by accumulating rare mutations. This hypothesis suggested that leukemia originated in blood stem cells because they live longer than regular blood cells, which only live up to a few weeks at most, not long enough to acquire the amount of rare mutations necessary to become cancerous. Blood stem cells, however, are capable of self-renewal, surviving in the body throughout an organism’s lifetime. Because the hypothesis has been difficult to test, it has remained controversial.

The main challenges have been to identify the protein-coding mutations in several acute myeloid leukemias, and then to isolate and analyze the rare, pre-cancerous hematopoietic, or residual, stem cells to determine which, if any, of the leukemia mutations were present in those “normal” stem cells, said Thomas Snyder, a chief scientist at ImmuMetrix and co-lead author of the paper.

In addition to their sequencing approach, the team also used high-throughput flow cytometry to identify markers specific for a patient’s healthy hematopoietic stem cells versus their leukemia stem cells and to isolate the very rare populations of pre-cancerous hematopoietic stem cells, said Snyder, a former post-doctoral researcher in Stanford bioengineer Stephen Quake's lab when the study was performed.

Together, Quake and Snyder developed those techniques to sort and study the genomes of the individual cells. “It is only when you can look at a single cell and determine its genotype that you can conclusively show the early stages in the evolution of the cancer,” said Snyder.

Reference

1. Jan, M. et. al. 2012. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 4:149, 1-11.