TY  - JOUR
A1  - Lück, Sonja C.
A1  - Ruß, Annika C.
A1  - Botzenhardt, Ursula
A1  - Schlenk, Richard Friedrich
A1  - Zobel, Kerry
A1  - Deshayes, Kurt
A1  - Vucic, Domagoj
A1  - Döhner, Hartmut
A1  - Döhner, Konstanze
A1  - Fulda, Simone
A1  - Bullinger, Lars
T1  - Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers
T2  - Oncotarget
N2  - 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.
KW  - smac mimetic
KW  - IAP proteins
KW  - apoptosis
KW  - acute myeloid leukemia (AML)
KW  - gene expression profiling (GEP)
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45838
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-458381
SN  - 1949-2553
N1  - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
VL  - 7
IS  - 31
SP  - 49539
EP  - 49551
PB  - Impact Journals LLC
CY  - [s. l.]
ER  -