Variable aldehyde dehydrogenase activity and effects on chemosensitivity of primitive human leukemic cells

Abstract

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 (ALDH^pos) 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 ALDH^pos and ALDH^neg. Interestingly, ALDH1A1 transcripts were highest in the ALDH^neg leukemic 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.