Leukemia stem cells stand apart from normal stem cells

A rare group of cancerous stem cells can continuously give rise to these abnormal blood cells, which characterize some types of leukemia
Image courtesy of Dr. John Krause, Tulane University School of Medicine

Some tumors harbor an elite group of cells that can continuously replenish themselves, forming a potent and evasive force to drive cancer growth. But in many cases, the origin of these "cancer stem cells" remains a mystery: Are they really normal stem cells in disguise, churning out countless copies of malignant cells instead of normal ones, or are they simply ordinary cells that have somehow co-opted the unique ability to self-renew? In an advance online publication appearing July 16 in Nature, a team of scientists reveals evidence that suggests the latter scenario may be the case in some types of leukemia, a cancer that arises in blood-forming tissues in the bone marrow.

The team, led by Dana-Farber Cancer Institute and Children’s Hospital researcher Scott Armstrong and including Broad scientists David Twomey, William Hahn and Todd Golub, induced leukemia in mice using an abnormal fusion protein derived from two different genes. This combination — the result of a molecular union between the mixed lineage leukemia (MLL) gene and the AF9 gene — produces a particularly aggressive form of leukemia in humans. The researchers specifically targeted the leukemia-causing fusion protein to a group of blood progenitor cells that, unlike the normal stem cells for the blood ("hematopoietic stem cells"), do not have the capacity for self-renewal and can give rise only to a limited range of blood cell types.

By carefully purifying and analyzing the rare cancer stem cells that were formed in this leukemic mouse model, the scientists discovered that the cells have some genetic similarities to normal hematopoietic stem cells. Using data from DNA microarrays, they compiled a list of more than 600 genes that are either switched on or off in both stem cell populations. Aside from this "self-renewal signature," the researchers noted that the leukemia stem cells are quite different from their normal counterparts, retaining many of the molecular characteristics of the progenitor cells from which they first originated. This suggests that the leukemia stem cells merely "borrowed" some key features from normal stem cells, by virtue of their shared genetic program, but otherwise, are most like typical cells that lack the ability to proliferate indefinitely.

The scientists analyzed the dynamics of the self-renewal signature and discovered a hierarchical pattern of gene activity, with some genes turning on very early in the development of leukemia stem cells and others much later. By inhibiting one of these early genes, researchers found that they could interfere with the stem cell-like behavior of the leukemia stem cells, which indicates that at least some features of the signature are essential for self-renewal. In addition, the scientists discovered that many of the genes that make up the signature — derived from analyses of mouse leukemia stem cells — are also found in leukemia stem cells in humans.

While all of this may seem like stem cell semantics, determining the exact relationship between normal stem cells and cancer stem cells may have important implications for the design of new cancer therapies. Normal stem cells are a crucial component of many tissues in the body, including the blood. On the other hand, cancer stem cells seem to be refractory to current therapies, and are thought to be the reason why some tumors can be seemingly eradicated, only to re-emerge years later. Therefore, having the ability to selectively avoid normal stem cells, while simultaneously eliminating cancer stem cells, could prove to be a powerful and perhaps more effective weapon in the arsenal of cancer treatments.