Variable aldehyde dehydrogenase activity and effects on chemosensitivity of primitive human leukemic cells.
Aldehyde dehydrogenase (ALDH) activity is an established feature of primitive normal human hematopoietic cells, in which it has been associated with a high expression of the 1A1 isoform of ALDH. High ALDH 1A1 activity has been reported to also characterize cells that propagate malignant populations arising in other tissues, but the regulation and basis of ALDH activity in primary human leukemic cells has not been well studied. We obtained samples from patients with newly diagnosed acute myeloid leukemia (AML; n = 21) and chronic myeloid leukemia (CML; n = 8) and analyzed different phenotypically and functionally defined subsets for their ALDH activity using the ALDEFLUOR®kit and expression of the ALDH1A1 gene. We detected cells with high ALDH activity (ALDHpos) in all samples from AML and CML patients. These were consistently enriched in the CD34+population of these samples, but typically not in the CD34+CD38-subset. Leukemic cells with direct clonogenic activity in vitro or those able to repopulate the bone marrow of sublethally irradiated non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice were both ALDHposand ALDHneg. Interestingly, ALDH1A1 transcripts were highest in the ALDHnegleukemic cells and, in studies with leukemic cell lines, exposure to an inhibitor of ALDH activity variably affected sensitivity to daunorubicin. Cells with high ALDH activity are commonly found within the CD34+population of primary human leukemic cells but, unlike in normal hematopoietic tissues, do not selectively or consistently comprise those with proliferative potential or other distinct functional properties.
Department of Medicine III, University of Munich, Munich, Germany.
Anja
A
Bogen
CCC Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany.
Christian
C
Buske
Department of Medicine III, University of Munich, Munich, Germany.
Wolfgang
W
Hiddemann
Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
Stefan K
SK
Bohlander
Department of Medicine III, University of Munich, Munich, Germany. Electronic address: o.christ@onkologie-hamm.de.
Oliver
O
Christ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D014644:Genetic Variation; D006801:Humans; D016130:Immunophenotyping; D007938:Leukemia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D050697:Retinal Dehydrogenase; D014158:Transcription, Genetic; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D000970:Antineoplastic Agents; D015415:Biomarkers; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase