Stem cells are endowed with the ability to self-renew, that means to give rise to other cells with the same potential to regenerate a tissue. Recently, we found a gene that also regulates this mechanism. In addition, expression of high levels of this gene can reduce the number of stem cells in the bone marrow, breast and the brain. This gene is expressed in the Chromosome 21 and hence can potentially contribute to the pathology of people with Down Syndrome (people with Down Syndrome has three copies of Chromosome 21). In line with that, we now observe that mouse models for Down Syndrome have fewer stem cells in their bone marrow, breast and brain. The same is true for human Down’s Syndrome. This work was published in Nature during the last year of funding. Outcomes from this study have begun to shed more light in understanding not only the normal process of stem cell maintenance, but also in deciphering the complex biology underlying Down Syndrome. In particular, our third year results demonstrate why Down Syndrome patients have a defect in learning. This suggests that pharmacologic agents that inhibit the function of this gene might ameliorate the pathology of Down Syndrome. Another important aspect of our research on this pertains to cancer development: indeed cancer initiating cells take advantage of the normal self-renewal machinery to proliferate without restraint. Data generated in the third year of funding show that high levels of this gene counteract some solid tissue tumors, putting a brake on cancer cells proliferation. These studies will give hint to alternative strategies for cancer treatment.