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 Blood, 15 October 2007, Vol. 110, No. 8, pp. 3005-3014.
Prepublished online as a Blood First Edition Paper on September 20, 2007; DOI 10.1182/blood-2007-03-079368.

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NEOPLASIA

The molecular signature of MDS stem cells supports a stem-cell origin of 5q– myelodysplastic syndromes

Lars Nilsson1, Patrik Edén2, Eleonor Olsson3, Robert Månsson1, Ingbritt Åstrand-Grundström1, Bodil Strömbeck4, Kim Theilgaard-Mönch5, Kristina Anderson1, Robert Hast6, Eva Hellström-Lindberg7, Jan Samuelsson8, Gösta Bergh9, Claus Nerlov1,10, Bertil Johansson4, Mikael Sigvardsson1, Åke Borg3, and Sten Eirik W. Jacobsen1

1 Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden; 2 Complex Systems Division, Department of Theoretical Physics, Lund University, Lund, Sweden; 3 DNA Microarray Resource Center, Department of Oncology, Lund University, Lund, Sweden; 4 Department of Clinical Genetics, Lund University, Lund, Sweden; 5 Granulocyte Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 6 Hematology Center, Karolinska University Hospital, Stockholm, Sweden; 7 Department of Medicine, Division of Hematology, Karolinska University Hospital (Huddinge), Stockholm, Sweden; 8 Department of Medicine, South Hospital, Karolinska Institute, Stockholm, Sweden; 9 Department of Medicine, Helsingborg Hospital, Sweden; and 10 European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo, Italy

Global gene expression profiling of highly purified 5q-deleted CD34+CD38–Thy1+ cells in 5q– myelodysplastic syndromes (MDSs) supported that they might originate from and outcompete normal CD34+CD38–Thy1+ hematopoietic stem cells. Few but distinct differences in gene expression distinguished MDS and normal stem cells. Expression of BMI1, encoding a critical regulator of self-renewal, was up-regulated in 5q– stem cells. Whereas multiple previous MDS genetic screens failed to identify altered expression of the gene encoding the myeloid transcription factor CEBPA, stage-specific and extensive down-regulation of CEBPA was specifically observed in MDS progenitors. These studies establish the importance of molecular characterization of distinct stages of cancer stem and progenitor cells to enhance the resolution of stage-specific dysregulated gene expression.


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