L. Nilsson, P. Edén, E. Olsson, R. Månsson, I. Åstrand-Grundström, B. Strömbeck, K. Theilgaard-Moench, R. Hast, E. Hellström-Lindberg, J. Samuelsson, G. Bergh, B. Johansson, M. Sigvardsson, Å. Borg and S.E.W. Jacobsen A Distinct Molecular Signature of Purified Cancer Stem Cells: Evidence for a Hematopoietic Stem Cell Origin of 5q- Syndrome submitted Summary Herein we present the first global gene expression profile of a purified cancer stem cell (CSC) population. Constituting 0.08% of bone marrow cells, CD34+CD38-Thy1+ cells represent the CSCs in myelodysplastic syndromes (MDS) with an isolated deletion of the long arm of chromosome 5 (5q- syndrome). The gene expression pattern of 5q- CD34+CD38-Thy1+ cells supports that 5q- stem cells originate in and outcompete normal CD34+CD38-Thy1+ stem cells. However, a few distinct differences in gene expression distinguish 5q- and normal CD34+CD38-Thy1+ stem cells. BMI1, a critical regulator of self-renewal is up-regulated in 5q- stem cells, as is the myeloid transcription factor CEBPα. These and other changes in gene expression are specific for 5q- CD34+CD38-Thy1+ stem cells, emphasizing the importance of specifically identifying, characterizing and eventually targeting CSCs. Significance Cancer cells and normal stem cells share the unique property of self-renewal. Compelling evidence has emerged for cancer cells being organized in a hierarchical manner, in which infrequent CSCs at the top of the hierarchy, are required as well as sufficient for sustained replenishment of the more short-lived progenitors, which constitute the bulk of the tumor. Therefore, specific identification and therapeutic targeting of CSCs will be of fundamental importance towards the goal of eradicating cancers. We have identified and purified the CSCs in 5q- syndrome and demonstrate that they originate in normal stem cells. Gene expression profiling of the 5q- stem cells identified BMI1 and CEBPα as genes uniquely up-regulated in 5q- stem cells, two genes known to be deregulated in leukemia. LU TP 05-19