Zhang J, Grindley JC, Yin T, et al. PTEN maintains hematopoietic stem cells and acts in lineage choice and leukemia prevention. Nature 2006;441:518-522.

Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes hematopoietic stem cells from leukemia-initiating cells. Nature 2006;441:475-482.

Don’t we wish sometimes that cancerous stem cells would just hold up a sign and say “Here I am?” Wouldn’t it make life a lot easier, especially for transplant physicians, if normal hematopoietic stem cells could be distinguished from malignant stem cells? Well, we’re not quite there yet but we may be starting to unlock some of the clues. Two mouse models recently reported in Nature implicate PTEN as a major regulatory switch in maintaining normal hematopoietic stem cell function. In their mouse model, Zhang and colleagues deleted exon 5 of the PTEN gene, which contains the lipid phosphatase domain, leading to PTEN deficiency. Their mice displayed a decline in the number of hematopoietic stem cells, a diminished self-renewal capacity, an increase in the number of colony-forming unit cells in the spleen and peripheral blood (with stable numbers of colony-forming unit cells in the bone marrow), a decrease in the number of common lymphocyte progenitors, and an increase in the peripheral blood monocytes and granulocytes. The end result culminated in PTEN-deficient mice developing a myeloproliferative disorder. Further, the PTEN-deleted cells could be transferred to irradiated recipient mice with subsequent disease development, evidence that they are “cancer stem cells.” Yilmaz and colleagues demonstrated that the leukemia-initiating stem cell could be distinguished from a normal hematopoietic stem cell by a differential response to rapamycin. In other words, dependency on normal levels of PTEN just might be the neon sign that says normal vs. leukemic.

What is PTEN anyway? PTEN is a tumor suppressor gene which is defective in a vast array of human cancers. PTEN is a phosphatase that negatively regulates signaling through the phosphatidylinositol-3-OH-kinase (PI3K) pathway, inhibiting survival and proliferation. More and more studies are demonstrating that both the Ras and the PI3K pathways are able to converge on and activate mTOR (mammalian target of rapamycin) to stimulate cell growth1,2 . Rapamcyin has long been approved for clinical use as an immunosuppressant. A number of newer rapamycin analogues are in various clinical testing phases. The study by Yilmaz and colleagues showed that normal hematopoietic stem cells were unable to maintain themselves without PTEN, in contrast to their leukemic counterparts. But these effects were mediated almost exclusively through mTOR, because they could be inhibited by rapamycin. Rapamycin, administered to these mice, not only depleted the leukemia-initiating cells, but also restored function to the normal hematopoietic stem cells. Could it be that simple in human leukemias? Likely not as PI3K signals through a multitude of other effectors besides mTOR. But it will certainly be intriguing to find out in future human clinical trials whether mTOR inhibitors can, in fact, differentially affect normal vs. leukemic stem cells.

1.
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumor cell growth. Nature 2006;441:424-430.
2.
Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K path-way as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006;6:184-192.

Competing Interests

Dr. Emanuel indicated no relevant conflicts of interest.