Heterogeneity of leukemia stem cell candidates at diagnosis of acute myeloid leukemia and their clinical significance.
Leukemia stem cell candidates (LSCC) can be enriched from patients with acute myeloid leukemia by high aldehyde dehydrogenase (ALDH) activity and CD34 expression. We have previously demonstrated the leukemia-initiating activity of ALDH(bright) cells in xenograft transplantation models, as well as in vitro. Applying single-cell long-term culture-initiating cell assays, we have correlated the functional properties of individual cells within this LSCC population and the respective phenotypes. To define their biologic significance, we also analyzed the relationship between LSCC at diagnosis to long-term clinical outcomes. The median percentage of ALDH(bright) cells among 101 acute myeloid leukemia patients was 0.51% (range, 0.01-12.90%). Single-cell long-term culture-initiating cell assays, followed by genetic analysis of the progeny cells, showed that the leukemia-initiating activity was found in the ALDH(bright)/CD34(high) subset and, to a lesser extent, in ALDH(bright)/CD34(low) or ALDH(bright)/CD34(-) subsets. Nevertheless, the frequency of ALDH(bright) cells at diagnosis correlated significantly with the persistence of leukemia after induction chemotherapy (n = 84, Spearman R = 0.3261; p < 0.0025). In the multivariate model, frequency of ALDH(bright) cells was the strongest prognostic marker (p = 0.0095) affecting overall survival (hazard ratio = 9.107). LSCC are heterogeneous and best reflected by ALDH activity. The frequency of ALDH(bright) cells at diagnosis is a significant prognostic marker for acute myeloid leukemia.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Dan
D
Ran
Mario
M
Schubert
Isabel
I
Taubert
Volker
V
Eckstein
Frauke
F
Bellos
Anna
A
Jauch
Hui
H
Chen
Thomas
T
Bruckner
Rainer
R
Saffrich
Patrick
P
Wuchter
Anthony D
AD
Ho
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D016016:Proportional Hazards Models
D018952:Antigens, CD34; D000444:Aldehyde Dehydrogenase