Cancer is, to a large degree, a disease of stem cells. When stem cells acquire particular mutations, they lose their controls on cell division and begin to divide uncontrollably. Several different studies have established that several types of cancers result from abnormal stem cells. Blood cancers, for example, form when stem cells accrue rare genetic mutations, according a new study. This discovery overturns the traditional view that blood cancers can originate from any blood cell, and it could conceivably help to prevent relapses in leukemia patients.
Stanford University researchers have identified the origins of leukemia. They used so-called “next-generation sequencing” techniques and various other methods to identify rare, pre-cancerous, blood stem cells in six individuals with acute myeloid leukemia. After identifying these pre-cancerous cells, they compared the genetic sequences from the pre-cancerous blood stem cells to the sequences of the same chromosomal regions from the patients’ leukemia-plagued stem cells. This analysis revealed the exact order of rare mutations that blood stem cells accrued in order to become cancerous.
Stanford hematologist Ravi Majeti, co-lead author of the study, commented: “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.”
Scientists have suspected for the last few decades that cancer stem cells, and in particular leukemia stem cells, lead to cancer. In 2005, a Stanford pathologist named Irving Weissman added a twist to this idea when he proposed that normal blood stem cells become cancerous stem cells by accumulating rare mutations. Weissman’s hypothesis suggested that leukemia originated in blood stem cells. Weissman’s hypothesis makes sense of a simple fact; blood stem cells live much longer than regular blood cells, which only live up to a few weeks at most. A few weeks is simply not enough time, to acquire the number of rare mutations necessary to become cancerous. Since blood stem cells are capable of self-renewal, they survive in the body throughout the lifetime of an organism. Unfortunately, such a hypothesis, despite its great explanatory power, is very difficult to directly test, and, therefore, has remained controversial.
The best way to test Weissman’s hypothesis is to identify the protein-coding mutations in several acute myeloid leukemias, and then isolate and analyze the rare, pre-cancerous stem cells to determine which, of the leukemia mutations were present in those pre-cancerous stem cells.
In addition to their sequencing approach, this team also used high-throughput flow cytometry to identify markers specific to a patient’s healthy blood cell-making stem cells versus their leukemia stem cells in order to isolate the very rare populations of pre-cancerous stem cells.
These techniques were pioneered by Thomas Snyder, who is a chief scientist at ImmuMetrix and co-lead author of this paper. Snyder worked as a post-doctoral researcher in the laboratory of Stanford bioengineer Stephen Quake when this he collaborated on this study. Together, Quake and Snyder developed those techniques to sort and study the genomes of each individual cell. “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.