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Acute Leukemias

Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups

Leukemia volume 25, pages 1728–1738 (2011)Cite this article

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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.

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Acknowledgements

We thank Sabine Renz and Anna Siegmund for excellent technical assistance with Ficoll gradient separation of primary CBF AML samples. We are grateful for Juan Du's help in establishing mutational screening assays. Furthermore, BV6 was kindly supplied by Genentech. This study was supported in part by the Deutsche José Carreras Stiftung e.V. (DJCLS R 08/32f) and the German Research Foundation (DFG DO 704/3-1); LB was supported in part by the German Research Foundation (Heisenberg-Stipendium BU 1339/3-1) and SF was supported in part by the German Research Foundation, Deutsche José Carreras Stiftung e.V., the EU (ApopTrain, APO-SYS) and IAP16/8.

Author contributions

SCL designed the research, performed research, analyzed and interpreted data, and wrote the manuscript. ACR designed the research, collected, analyzed and interpreted data, and reviewed the manuscript. UB, PP and RFS collected data and reviewed the manuscript. HD and KD designed research and reviewed the manuscript. SF designed the research, contributed vital reagents, analyzed data and reviewed the manuscript. LB designed the research, interpreted data and wrote the manuscript.

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  1. Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany

    S C Lück, A C Russ, U Botzenhardt, P Paschka, R F Schlenk, H Döhner, K Döhner & L Bullinger

  2. Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany

    S Fulda

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  1. S C Lück
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Lück, S., Russ, A., Botzenhardt, U. et al. Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups. Leukemia 25, 1728–1738 (2011). https://doi.org/10.1038/leu.2011.154

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