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


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).


CONCLUSIONS
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.
Ran
Dan
D
Department of Internal Medicine V, University of Heidelberg, Heidelberg 69120, Germany.
Schubert
Mario
M
Pietsch
Larissa
L
Taubert
Isabel
I
Wuchter
Patrick
P
Eckstein
Volker
V
Bruckner
Thomas
T
Zoeller
Margot
M
Ho
Anthony D
AD
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007942:Leukemia, Experimental / Q000201:enzymology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D011379:Prognosis; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D055815:Young Adult
D018952:Antigens, CD34; D000444:Aldehyde Dehydrogenase