title: Targeted therapy for a subset of acute myeloid leukemias that lack expression of aldehyde dehydrogenase 1A1.
abstract: Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that approximately 25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1-subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1-cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide. In contrast, normal hematopoietic stem cells were relatively resistant to these compounds. Using a murine xenotransplant model to emulate a clinical treatment strategy, established ALDH1A1-leukemias were also sensitive toin vivotreatment with cyclophosphamide combined with arsenic trioxide. These results demonstrate that targeting ALDH1A1-leukemic cells with toxic ALDH1A1 substrates such as arsenic and cyclophosphamide may be a novel targeted therapeutic strategy for this subset of acute myeloid leukemias.
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA maura.gasparetto@ucdenver.edu.
authors.forename: Maura
authors.initials: M
authors.lastname: Gasparetto
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pei
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Minhajuddin
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Nabilah
authors.initials: N
authors.lastname: Khan
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: Genomics Research Center, University of Rochester, NY, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Myers
authors.affiliation: Genomics Research Center, University of Rochester, NY, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Ashton
authors.affiliation: Department of Medicine, University of Rochester Medical Center, NY, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Department of Environmental Health Sciences, Yale University, New Haven, CT, USA.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Humphries
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO, USA.
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Smith
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods*; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D058990:Molecular Targeted Therapy; D010087:Oxides / Q000627:therapeutic use; D050697:Retinal Dehydrogenase
chemical_list: D001152:Arsenicals; D010087:Oxides; D003520:Cyclophosphamide; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D000077237:Arsenic Trioxide