Mitochondrial BAX determines the predisposition to apoptosis in human AML

Frank Reichenbach; Cornelius Wiedenmann; Enrico Schalk; Diana Becker; Kathrin Funk; Peter Scholz-Kreisel; Franziska Todt; Denise Wolleschak; Konstanze Döhner; Jens U. Marquardt; Florian Heidel; Frank Edlich

doi:10.1158/1078-0432.CCR-16-1941

Mitochondrial BAX determines the predisposition to apoptosis in human AML

Frank Reichenbach^*, Cornelius Wiedenmann, Enrico Schalk, Diana Becker, Kathrin Funk, Peter Scholz-Kreisel, Franziska Todt, Denise Wolleschak, Konstanze Döhner, Jens U. Marquardt, Florian Heidel, Frank Edlich

^*Corresponding author for this work

Department of Internal Medicine I

26 Citations (Scopus)

Abstract

Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path."

Original language	English
Journal	Clinical Cancer Research
Volume	23
Issue number	16
Pages (from-to)	4805-4816
Number of pages	12
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-16-1941
Publication status	Published - 15.08.2017

Funding

This work was supported by the DFG Emmy Noether program, the Collaborative Research Cluster (CRC) 746, the Else Kr?ner-Fresenius-Stiftung, the Wilhelm Sander-Stiftung, the Spemann Graduate School of Biology and Medicine (SGBM, GSC-4) and the Centre for Biological Signalling Studies (BIOSS, EXC-294) funded by the Excellence Initiative of the German Federal and State Governments (F. Reichenbach, C. Wiedenmann, F. Todt, F. Edlich). F. Heidel was supported by a grant of the German Research Foundation, Collaborative Research Cluster (CRC) 854 (Project A20), the ProExcellence Research Initiative "RegenerAging" (State of Thuringia), the Thuringian country programme ProExzellenz (RegenerAging - FSU-I-03/14) of the Thuringian Ministry for Research (TMWWDG), and the German Jose-Carreras Leukemia Society (DJCLS SP12/08). K. D?hner was supported by a grant of the German Research Foundation, Collaborative Research Cluster (CRC) 1074 (Project B3) and the AMLSG study group. J.U. Marquardt is supported by the German Cancer Aid (DKH 110989), the Wilhelm Sander-Stiftung, and the Volkswagen Foundation (Lichtenberg program). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. This work was supported by the DFG Emmy Noether program, the Collaborative Research Cluster (CRC) 746, the Else Kro€ner-Fresenius-Stiftung, the Wilhelm Sander-Stiftung, the Spemann Graduate School of Biology and Medicine (SGBM,GSC-4)andtheCentreforBiologicalSignallingStudies(BIOSS,EXC-294) funded by the Excellence Initiative of the German Federal and State Governments (F. Reichenbach,C.Wiedenmann,F.Todt,F.Edlich).F.Heidel wassupportedbya grant of the German Research Foundation, Collaborative Research Cluster (CRC) 854 (Project A20), the ProExcellence Research Initiative "RegenerAging" (State of Thuringia), the Thuringian country programme ProExzellenz (RegenerAging - FSU-I-03/14) of the Thuringian Ministry for Research (TMWWDG), and the German Jose-Carreras Leukemia Society (DJCLS SP12/08). K. Do€hner was supported by a grant of the German Research Foundation, Collaborative Research Cluster (CRC) 1074 (Project B3) and the AMLSG study group. J.U. Marquardt is supported by the German Cancer Aid (DKH 110989), the Wilhelm Sander-Stiftung, and the Volkswagen Foundation (Lichtenberg program).

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10.1158/1078-0432.CCR-16-1941

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title = "Mitochondrial BAX determines the predisposition to apoptosis in human AML",

abstract = "Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final {"}common path.{"}",

author = "Frank Reichenbach and Cornelius Wiedenmann and Enrico Schalk and Diana Becker and Kathrin Funk and Peter Scholz-Kreisel and Franziska Todt and Denise Wolleschak and Konstanze D{\"o}hner and Marquardt, \{Jens U.\} and Florian Heidel and Frank Edlich",

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doi = "10.1158/1078-0432.CCR-16-1941",

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T1 - Mitochondrial BAX determines the predisposition to apoptosis in human AML

AU - Reichenbach, Frank

AU - Wiedenmann, Cornelius

AU - Schalk, Enrico

AU - Becker, Diana

AU - Funk, Kathrin

AU - Scholz-Kreisel, Peter

AU - Todt, Franziska

AU - Wolleschak, Denise

AU - Döhner, Konstanze

AU - Marquardt, Jens U.

AU - Heidel, Florian

AU - Edlich, Frank

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path."

AB - Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path."

UR - https://www.scopus.com/pages/publications/85028036047

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 16

ER -

Mitochondrial BAX determines the predisposition to apoptosis in human AML

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