Aldehyde dehydrogenase activity among primary leukemia cells is associated with stem cell features and correlates with adverse clinical outcomes

Ran, Dan; Schubert, Mario; Pietsch, Larissa; Taubert, Isabel; Wuchter, Patrick; Eckstein, Volker; Bruckner, Thomas; Zoeller, Margot; Ho, Anthony D.

doi:10.1016/j.exphem.2009.10.001

« Previous Next »Experimental Hematology
Volume 37, Issue 12 , Pages 1423-1434, December 2009

Aldehyde dehydrogenase activity among primary leukemia cells is associated with stem cell features and correlates with adverse clinical outcomes

Dan Ran
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
- Drs. Ran and Schubert contributed equally to this work.
Mario Schubert
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
- Drs. Ran and Schubert contributed equally to this work.
Larissa Pietsch
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
Isabel Taubert
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
Patrick Wuchter
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
Volker Eckstein
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
Thomas Bruckner
- Department of Biometry, University of Heidelberg, Heidelberg, Germany
Margot Zoeller
- Department of Surgery, Section for Tumor Cell Biology, University of Heidelberg, Heidelberg, Germany
Anthony D. Ho
- Department of Internal Medicine V, 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

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 (ALDH^br), 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 ALDH^br 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 ALDH^br 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 ALDH^br 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 ALDH^br and CD34⁺. They demonstrated functional characteristics of LSC and high percentages of these cells among the leukemia cells correlated significantly with poor clinical outcome.