title: Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups.
abstract: Core-binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the CBF, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, about 40% of patients relapse and the current classification system does not fully reflect this clinical heterogeneity. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences and identified apoptotic signaling, MAPKinase signaling and chemotherapy-resistance mechanisms among the most significant differentially regulated pathways. We now tested different inhibitors of the respective pathways in a cell line model (six cell lines reflecting the CBF subgroup-specific gene expression alterations), and found apoptotic signaling to be differentiating between the CBF subgroup models. In accordance, primary samples from newly diagnosed CBF AML patients (n=23) also showed differential sensitivity to in vitro treatment with a Smac mimetic such as BV6, an antagonist of inhibitor of apoptosis (IAP) proteins, and ABT-737, a BCL2 inhibitor. Furthermore, GEP revealed the BV6-resistant cases to resemble the previously identified unfavorable CBF subgroup. Thus, our current findings show deregulated IAP expression and apoptotic signaling to differentiate clinically relevant CBF subgroups, which were independent of known molecular markers, thereby providing a starting point for novel therapeutic approaches.
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: S C
authors.initials: SC
authors.lastname: Lück
authors.forename: A C
authors.initials: AC
authors.lastname: Russ
authors.forename: U
authors.initials: U
authors.lastname: Botzenhardt
authors.forename: P
authors.initials: P
authors.lastname: Paschka
authors.forename: R F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D050660:Core Binding Factors / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C582180:BV6 peptide; D050660:Core Binding Factors; D017931:DNA Primers; D009842:Oligopeptides