Aldehyde dehydrogenase activity among primary leukemia cells is associated with stem cell features and correlates with adverse clinical outcomes
Received 10 August 2009; received in revised form 5 October 2009; accepted 5 October 2009. published online 12 October 2009.
Objective
Animal models have provided evidence for the existence of leukemia stem cells (LSC). However, prospective isolation of human LSC from patients with acute myeloid leukemia (AML), as well as the assessment of their clinical significance, has remained a major challenge.
Materials and Methods
We have studied the functional characteristics of a subset of leukemia cells that expressed CD34 and high aldehyde dehydrogenase activity (ALDHbr), which was freshly isolated from the mononuclear cells at the time of diagnosis from the marrow of 68 consecutive patients suffering from AML.
Results
The percentage of ALDHbr cells ranged from 0.01% to 16.0% with a median of 0.5%. Compared to their counterparts with low aldehyde dehydrogenase activity from the same individual patients, the ALDHbr population showed a significantly higher affinity to human mesenchymal stromal cells (n=12; p<0.01), a more than twofold higher proportion of slow-dividing and quiescent cells (n=4; p<0.05), higher numbers of long-term culture-initiating cell colonies in vitro (n=25; p<0.01), and an enhanced engraftment in the nonobese diabetic/severe combined immunodeficient mouse model (n=3; p<0.05). Above all, we found that the frequency of ALDHbr cells correlated significantly with diminished survival probability (p=0.025) and with adverse cytogenetic factors (p<0.05).
Conclusion
A small proportion of leukemia cells derived from the marrow of patients with AML were ALDHbr and CD34+. They demonstrated functional characteristics of LSC and high percentages of these cells among the leukemia cells correlated significantly with poor clinical outcome.
aDepartment of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
bDepartment of Biometry, University of Heidelberg, Heidelberg, Germany
cDepartment of Surgery, Section for Tumor Cell Biology, University of Heidelberg, Heidelberg, Germany
Offprint requests to: Anthony D. Ho, M.D., Department of Internal Medicine V, Im Neuenheimer Feld 410, Heidelberg 69120, Germany
∗ Drs. Ran and Schubert contributed equally to this work.
ABSTRACT