BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells

Cairns, 2011, Regulation of cancer cell metabolism, Nat. Rev. Cancer, 11, 85, 10.1038/nrc2981 Chen, 2007, Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells, Cell Death Differ., 14, 1617, 10.1038/sj.cdd.4402165 Del Poeta, 2003, Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML), Blood, 101, 2125, 10.1182/blood-2002-06-1714 Delia, 1992, bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells, Blood, 79, 1291, 10.1182/blood.V79.5.1291.1291 Diehn, 2009, Association of reactive oxygen species levels and radioresistance in cancer stem cells, Nature, 458, 780, 10.1038/nature07733 Eppert, 2011, Stem cell gene expression programs influence clinical outcome in human leukemia, Nat. Med., 17, 1086, 10.1038/nm.2415 Falini, 2007, Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features, Blood, 109, 874, 10.1182/blood-2006-07-012252 Hole, 2010, Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells, Blood, 115, 1238, 10.1182/blood-2009-06-222869 Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells, Nat. Med., 12, 446, 10.1038/nm1388 Jang, 2007, A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche, Blood, 110, 3056, 10.1182/blood-2007-05-087759 Konopleva, 2006, Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia, Cancer Cell, 10, 375, 10.1016/j.ccr.2006.10.006 Magee, 2012, Cancer stem cells: impact, heterogeneity, and uncertainty, Cancer Cell, 21, 283, 10.1016/j.ccr.2012.03.003 Nakajima, 2012, Metabolic symbiosis in cancer: Refocusing the Warburg lens, Mol. Carcinog. Saito, 2010, Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML, Nat. Biotechnol., 28, 275, 10.1038/nbt.1607 Sarry, 2011, Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice, J. Clin. Invest., 121, 384, 10.1172/JCI41495 Simsek, 2010, The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche, Cell Stem Cell, 7, 380, 10.1016/j.stem.2010.07.011 Smith, 2000, Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell, Proc. Natl. Acad. Sci. USA, 97, 10032, 10.1073/pnas.170209797 Tothova, 2007, FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress, Cell, 128, 325, 10.1016/j.cell.2007.01.003 Trachootham, 2008, Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism, Blood, 112, 1912, 10.1182/blood-2008-04-149815 Trachootham, 2009, Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?, Nat. Rev. Drug Discov., 8, 579, 10.1038/nrd2803 van Delft, 2006, The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized, Cancer Cell, 10, 389, 10.1016/j.ccr.2006.08.027 Varum, 2011, Energy metabolism in human pluripotent stem cells and their differentiated counterparts, PLoS ONE, 6, e20914, 10.1371/journal.pone.0020914 Vlashi, 2011, Metabolic state of glioma stem cells and nontumorigenic cells, Proc. Natl. Acad. Sci. USA, 108, 16062, 10.1073/pnas.1106704108 Warburg, 1956, On the origin of cancer cells, Science, 123, 309, 10.1126/science.123.3191.309 Westermann, 2010, Mitochondrial fusion and fission in cell life and death, Nat. Rev. Mol. Cell Biol., 11, 872, 10.1038/nrm3013