title: Preferential induction of apoptosis for primary human leukemic stem cells.
abstract: Acute myelogenous leukemia (AML) is typically a disease of stem progenitor cell origin. Interestingly, the leukemic stem cell (LSC) shares many characteristics with normal hematopoietic stem cells (HSCs) including the ability to self-renew and a predominantly G(0) cell-cycle status. Thus, although conventional chemotherapy regimens often ablate actively cycling leukemic blast cells, the primitive LSC population is likely to be drug-resistant. Moreover, given the quiescent nature of LSCs, current drugs may not effectively distinguish between malignant stem cells and normal HSCs. Nonetheless, based on recent studies of LSC molecular biology, we hypothesized that certain unique properties of leukemic cells could be exploited to induce apoptosis in the LSC population while sparing normal stem cells. In this report we describe a strategy using treatment of primary AML cells with the proteasome inhibitor carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal (MG-132) and the anthracycline idarubicin. Comparison of normal and leukemic specimens using in vitro culture and in vivo xenotransplantation assays shows that the combination of these two agents induces rapid and extensive apoptosis of the LSC population while leaving normal HSCs viable. Molecular genetic studies using a dominant-negative allele of inhibitor of nuclear factor kappaB (IkappaBalpha) demonstrate that inhibition of nuclear factor kappaB (NF-kappaB) contributes to apoptosis induction. In addition, gene-expression analyses suggest that activation of p53-regulated genes are also involved in LSC apoptosis. Collectively, these findings demonstrate that malignant stem cells can be preferentially targeted for ablation. Further, the data begin to elucidate the molecular mechanisms that underlie LSC-specific apoptosis and suggest new directions for AML therapy.
authors.affiliation: Blood and Marrow Transplant Program, Markey Cancer Center, Division of HematologyOncology, University of Kentucky Medical Center, Lexington, KY 40536-0093 USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.forename: Carol F
authors.initials: CF
authors.lastname: Swiderski
authors.forename: Dianna S
authors.initials: DS
authors.lastname: Howard
authors.forename: Barry A
authors.initials: BA
authors.lastname: Grimes
authors.forename: Randall M
authors.initials: RM
authors.lastname: Rossi
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Szilvassy
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
mesh_terms: D000208:Acute Disease; D000483:Alleles; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006085:Graft Survival; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D015255:Idarubicin / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D015255:Idarubicin