title: Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers.
abstract: Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Lueck
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Annika C
authors.initials: AC
authors.lastname: Russ
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Botzenhardt
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.affiliation: Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.affiliation: Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003561:Cytarabine / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D000090243:Nucleophosmin; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C000716967:NPM1 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D003561:Cytarabine; D000090243:Nucleophosmin
keywords: IAP proteins; acute myeloid leukemia (AML); apoptosis; gene expression profiling (GEP); smac mimetic