Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

被引:24
作者
Reichenbach, Frank [1 ,2 ,3 ]
Wiedenmann, Cornelius [1 ]
Schalk, Enrico [4 ]
Becker, Diana [5 ]
Funk, Kathrin [1 ]
Scholz-Kreisel, Peter [6 ]
Todt, Franziska [1 ]
Wolleschak, Denise [4 ]
Doehner, Konstanze [7 ]
Marquardt, Jens U. [5 ]
Heidel, Florian [8 ,9 ,10 ]
Edlich, Frank [1 ,11 ]
机构
[1] Univ Freiburg, Inst Biochem & Mol Biol, Freiburg, Germany
[2] SGBM, Spemann Grad Sch Biol & Med, Freiburg, Germany
[3] Univ Freiburg, Fac Biol, Freiburg, Germany
[4] Otto von Guericke Univ, Dept Hematol & Oncol, Med Ctr, Magdeburg, Germany
[5] Johannes Gutenberg Univ Mainz, Dept Med, Mainz, Germany
[6] Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, Mainz, Germany
[7] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
[8] Friedrich Schiller Univ, Jena Univ Hosp, Internal Med Hematol & Oncol 2, Jena, Germany
[9] Friedrich Schiller Univ, Med Fac, Jena, Germany
[10] Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany
[11] Univ Freiburg, Ctr Biol Signaling Studies, BIOSS, Freiburg, Germany
关键词
ACUTE MYELOID-LEUKEMIA; BCL-2; FAMILY-MEMBERS; PROGNOSTIC-SIGNIFICANCE; BH3-ONLY PROTEINS; BH3; DOMAINS; FLT3; CELLS; VARIABILITY; EXPRESSION; MUTATIONS;
D O I
10.1158/1078-0432.CCR-16-1941
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, mitochondriashifted 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." (C) 2017 AACR.
引用
收藏
页码:4805 / 4816
页数:12
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