Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors

Area of Science:

• Hematology
• Cancer Biology
• Pharmacology

Background:

• Acute myeloid leukemia (AML) patients often relapse after chemotherapy due to resistant leukemia stem cells (LSCs).
• LSCs, characterized by CD34+CD38- and aldehyde dehydrogenase activity (ALDH+), evade conventional treatments like cytarabine and anthracycline.
• Existing therapies exhibit significant toxicity to normal cells while sparing LSCs.

Purpose of the Study:

• To investigate the efficacy of dimethyl ampal thiolester (DIMATE), an ALDH inhibitor, against LSCs in AML.
• To assess DIMATE's selective toxicity towards LSCs compared to healthy hematopoietic stem cells.

Main Methods:

• Sorted CD34+CD38- subpopulations from AML patients and healthy donors were treated with DIMATE.
• Aldehyde dehydrogenase (ALDH) activity and cell viability were monitored using flow cytometry.
• Enzyme kinetics and in vivo studies in immunodeficient mice were performed.

Main Results:

• DIMATE is a competitive, irreversible inhibitor of ALDH1 and a potent inhibitor of ALDHs 1 and 3.
• DIMATE demonstrated significant cytotoxic activity against human AML cell lines and LSC-enriched populations.
• DIMATE eradicated human AML cells in vivo without toxicity to healthy mouse hematopoietic cells, preserving their self-renewal and differentiation capacity.

Conclusions:

• DIMATE selectively targets and eradicates LSCs in AML.
• DIMATE represents a promising therapeutic agent for AML, offering a strategy to overcome treatment resistance and relapse.
• DIMATE spares healthy hematopoietic stem cells, suggesting a favorable safety profile compared to conventional chemotherapy.