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Targeted Therapy of Acute Myeloid Leukemia pp 47–65Cite as

Roles of Apoptosis-Regulating Bcl-2 Family Genes in AML

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Part of the book series: Current Cancer Research ((CUCR))

Abstract

Among the cardinal features of malignancy is abrogation of cell death mechanisms, thus endowing cancer and leukemia cells with a selective survival advantage relative to normal cells. Genetic and epigenetic lesions that result in defects in cell death regulation represent an essential characteristic of acute myeloid leukemia (AML), promoting accumulation of leukemia cells by conferring tolerance to oncogene activation, cell cycle checkpoint defects, and genetic instability. Defects in cell death mechanisms also greatly contribute to resistance to cytotoxic anticancer drugs. Bcl-2 family proteins are central regulators of cell life and death, impacting both apoptotic and non-apoptotic cell death. The Bcl-2 family includes both cell survival- and death-promoting members, with the relative levels and activities of these proteins becoming imbalanced in favor of cell survival in AML and most other malignancies. The fundamental mechanisms of Bcl-2 family proteins and some of their roles in AML are reviewed in this chapter.

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References

  • Ahmed N, Sammons J, Hassan H (1999) Bcl-2 protein in human myeloid leukemia cells and its down-regulation during chemotherapy-induced apoptosis. Oncol Rep 6(2):403–407

    CAS  PubMed  Google Scholar 

  • Andreeff M, Jiang SW, Zhang X, Konopleva M, Estrov Z, Snell VE et al (1999) Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia 13:1881–1892

    CAS  PubMed  Google Scholar 

  • Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE et al (2006) Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci U S A 103:2809–2814

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bailly-Maitre B, Belgardt BF, Jordan SD, Coornaert B, von Freyend MJ, Kleinridders A et al (2010) Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance. J Biol Chem 285(9):6198–6207

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bernales S, McDonald KL, Walter P (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4(12):e423

    PubMed Central  PubMed  Google Scholar 

  • Bincoletto C, Saad STO, Soares de Silva E, Queiroz MLS (1999) Haematopoietic response and bcl-2 expression in patients with acute myeloid leukaemia. Eur J Haematol 62:38–42

    CAS  PubMed  Google Scholar 

  • Boatright KM, Salvesen GS (2003) Mechanisms of caspase activation. Curr Opin Cell Biol 15:725–731

    CAS  PubMed  Google Scholar 

  • Bouillet P, Strasser A (2002) BH3-only proteins—evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 115(Pt 8):1567–1574

    CAS  PubMed  Google Scholar 

  • Bradbury D, Zhu Y-M, Russell N (1994) Regulation of Bcl-2 expression and apoptosis in acute myeloblastic leukemia cells by granulocyte-macrophage colony-stimulating factor. Leukemia 8:786–791

    CAS  PubMed  Google Scholar 

  • Brimmell M, Mendiola R, Mangion J, Packham G (1998) Bax frameshift mutations in cell lines derived from human haemopoietic malignacies are associated with resistance to apoptosis and microsatellite instability. Oncogene 16:1803–1812

    CAS  PubMed  Google Scholar 

  • Campos L, Roualult J-P, Sabido O, Roubi N, Vasselon C, Archimbaud E et al (1993) High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096

    CAS  PubMed  Google Scholar 

  • Campos L, Oriol P, Sabido O, Guyotat D (1997) Simultaneous expression of P-glycoprotein and bcl-2 in acute. Leuk Lymphoma 27(1–2):119–125

    CAS  PubMed  Google Scholar 

  • Cardenas C, Miller RA, Smith I, Bui T, Molgo J, Muller M et al (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142(2):270–283

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14(2):193–204

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S et al (2004) BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15(3):355–356

    CAS  PubMed  Google Scholar 

  • Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/ reperfusion. J Biol Chem 276:30724–30728

    CAS  PubMed  Google Scholar 

  • Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM et al (2011) Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195(2):263–276

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ (2003) VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301:513–517

    CAS  PubMed  Google Scholar 

  • Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18(4):157–164

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37(3):299–310

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chipuk J, McStay G, Bharti A, Kuwana T, Clarke C, Siskind L et al (2012) Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148(5):845–848

    Google Scholar 

  • Criollo A, Maiuri MC, Tasdemir E, Vitale I, Fiebig AA, Andrews D et al (2007) Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ 14(5):1029–1039

    CAS  PubMed  Google Scholar 

  • Delia D, Aiello A, Formelli F, Fontanella E, Costa A, Miyashita T et al (1995) Regulation of apoptosis induced by N-(4-hydroxyphenyl) retinamide and effect of Bcl-2. Blood 85:359–367

    CAS  PubMed  Google Scholar 

  • Demaurex N, Distelhorst C (2003) Apoptosis—the calcium connection. Science 300(5616):65–67

    CAS  PubMed  Google Scholar 

  • Deng GL ane C, Kornblau S, Goodacre A, Snell V, Andreeff M et al (1998) Ratio of bcl-xshort to bcl-xlong is different in good- and poor-prognosis subsets of acute myeloid leukemia. Mol Med 4(3):158–164

    PubMed Central  CAS  PubMed  Google Scholar 

  • Deveraux QL, Reed JC (1999) IAP family proteins: suppressors of apoptosis. Genes Dev 13:239–252

    CAS  PubMed  Google Scholar 

  • Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J 18:5242–5251

    PubMed Central  CAS  PubMed  Google Scholar 

  • Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosova I et al (2002) Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage. Cell 111:51–62

    CAS  PubMed  Google Scholar 

  • Dipietrantonio A, Hsieh T-C, Wu JM (1996) Differential effects of retinoic acid (RA) and N –(4-hydroxyphenyl)retinamide (4-HPR) on cell growth, induction of differentiation, and changes in p34cdc2, bcl-2, and actin expression in the human promyelocytic hl-60 leukemic cells. Biochem Biophys Res Commun 224:837–842

    CAS  PubMed  Google Scholar 

  • Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW (2004) MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23(31):5301–5315

    CAS  PubMed  Google Scholar 

  • Dong D, Ko B, Baumeister P, Swenson S, Costa F, Markland F et al (2005) Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. Cancer Res 65(13):5785–5791

    CAS  PubMed  Google Scholar 

  • Droga-Mazovec G, Bojic L, Petelin A, Ivanova S, Romih R, Repnik U et al (2008) Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J Biol Chem 283(27):19140–19150

    CAS  PubMed  Google Scholar 

  • Elstner E, Linker-Israeli M, Umiel T, Le J, Grillier I, Said J et al (1996) Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cis-retinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells. Cancer Res 56(15):3570–3576

    CAS  PubMed  Google Scholar 

  • Fan G, Simmons MJ, Ge S, Dutta-Simmons J, Kucharczak J, Ron Y et al (2010) Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. Blood 115(17):3559–3569

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fernandez PM, Tabbara SO, Jacobs LK, Manning FC, Tsangaris TN, Schwartz AM et al (2000) Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59(1):15–26

    CAS  PubMed  Google Scholar 

  • Fesik SW (2000) Insights into programmed cell death through structural biology. Cell 103:273–282

    CAS  PubMed  Google Scholar 

  • Fox JL, Ismail F, Azad A, Ternette N, Leverrier S, Edelmann MJ et al (2010) Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO J 29(22):3853–3868

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD (2010) BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX. Mol Cell 40(3):481–492

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gozuacik D, Bialik S, Raveh T, Mitou G, Shohat G, Sabanay H et al (2008) DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ 15(12):1875–1886

    CAS  PubMed  Google Scholar 

  • He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z et al (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481(7382):511–515

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B et al (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312(5773):572–576

    CAS  PubMed  Google Scholar 

  • Holinger E, Chittenden T, Lutz R (1999) Bak BH3 Peptides antagonize Bcl-xL Function and induce apoptosis through cytochrome c-independent Activation of Caspases. J Biol Chem 274:13298–13304

    CAS  PubMed  Google Scholar 

  • Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14(9):1576–1582

    CAS  PubMed  Google Scholar 

  • Hunsberger JG, Machado-Vieira R, Austin DR, Zarate C, Chuang DM, Chen G et al (2011) Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience. Brain Res 1403:19–27

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jamora C, Dennert G, Lee AS (1996) Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci U S A 93(15):7690–7694

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC (1998) Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci U S A 95:4997–5002

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15(4):1126–1132

    PubMed Central  CAS  PubMed  Google Scholar 

  • Karakas T, Maurer U, Weidmann E, Miething C, Hoelzer D, Bergmann L (1998) High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia. Ann Oncol 9(2):159–165

    CAS  PubMed  Google Scholar 

  • Kasimirbauer S, Ottinger H, Meusers P, Beelen D, Brittinger G, Seeber S et al (1998) In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protien, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy. Exp Hematol 26(12):1111–1117

    CAS  Google Scholar 

  • Khwaja A (1999) Akt is more than just a bad kinase. Nature 401:33–34

    CAS  PubMed  Google Scholar 

  • Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7(12):1013–1030

    CAS  PubMed  Google Scholar 

  • Kim HR, Lee GH, Ha KC, Ahn T, Moon JY, Lee BJ et al (2008) Bax Inhibitor-1 Is a pH-dependent regulator of Ca2+ channel activity in the endoplasmic reticulum. J Biol Chem 283(23):15946–15955

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kitada S, Pedersen IM, Schimmer A, Reed JC (2002) Dysregulation of apoptosis genes in hematopeietic malignancies. Oncogene 21:3459–3474

    CAS  PubMed  Google Scholar 

  • Kiviluoto S, Schneider L, Luyten T, Vervliet T, Missiaen L, De Smedt H et al (2012) Bax Inhibitor-1 is a novel IP(3) receptor-interacting and -sensitizing protein. Cell Death Dis 3:e367

    PubMed Central  CAS  PubMed  Google Scholar 

  • Konopleva M, Andreeff M (2002) Mechanisms in drug resistance in AML. In: Murray D, Andersson BS (eds) Clinically relevant resisitance in cancer chemotherapy, Kluwer Academic Publishers, Norwell, pp 237–262

    Google Scholar 

  • Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE et al (2002) Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood 99:326–335

    CAS  PubMed  Google Scholar 

  • Kornblau SM, Thall PF, Estrov Z, Walterscheid M, Patel S, Theriault A et al (1999) The prognostic impact of BCL2 protein expression in acute myelogenous leukemia varies with cytogenetics. Clin Cancer Res 5:1758–1766

    CAS  PubMed  Google Scholar 

  • Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173

    CAS  PubMed  Google Scholar 

  • Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519

    CAS  PubMed  Google Scholar 

  • Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO et al (2006) Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 168(4):1299–1308; quiz 1404–1295

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lam D, Kosta A, Luciani MF, Golstein P (2008) The Inositol 1,4,5-Trisphosphate receptor is required to signal autophagic cell death. Mol Biol Cell 19(2):691–700

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lauria F, Raspadori D, Rondelli D, Ventura M, Fiacchini M, Visani G et al (1997) High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate. Leukemia 11(12):2075–2078

    CAS  PubMed  Google Scholar 

  • Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67(8):3496–3499

    CAS  PubMed  Google Scholar 

  • Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A 100(17):9946–9951

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee H, Rotolo JA, Mesicek J, Penate-Medina T, Rimner A, Liao WC et al (2011) Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS One 6(6):e19783

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 100(5):2432–2437

    PubMed Central  CAS  PubMed  Google Scholar 

  • Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115(10):2679–2688

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6(1):45–54

    CAS  PubMed  Google Scholar 

  • Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD et al (2000) Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289:1159–1164

    CAS  PubMed  Google Scholar 

  • Li G, Mongillo M, Chin KT, Harding H, Ron D, Marks AR et al (2009) Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186(6):783–792

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lin B, Kolluri SK, Lin F, Liu W, Han Y-H, Cao X et al (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor TR3/NGFI-B/Nur Cell 116:527–540

    CAS  PubMed  Google Scholar 

  • Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F et al (2009) BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell 33(6):679–691

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lisovsky M, Extrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V et al (1996) Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood 88(10):3987–3997

    CAS  PubMed  Google Scholar 

  • Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4(12):966–977

    CAS  PubMed  Google Scholar 

  • Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R et al (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18(24):3066–3077

    PubMed Central  CAS  PubMed  Google Scholar 

  • Maung ZT, MacLean FR, Reid MM, Pearson ADJ, Proctor SJ, Hamilton PJ et al (1994) The relationship between Bcl-2 expression and response to chemotherapy in acute leukemia. Br J Haematol 88:105–109

    CAS  PubMed  Google Scholar 

  • Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760

    CAS  PubMed  Google Scholar 

  • McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21(4):1249–1259

    PubMed Central  CAS  PubMed  Google Scholar 

  • Meiijerink JPP, Smetsers TFCM, Slöetjes AW, Linders EHP, Mensink EJBM (1995) Bax mutations in cell lines derived from hematological malignancies. Leukemia 9:1828–1832

    Google Scholar 

  • Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T et al (1998) Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 91:2991–2997

    CAS  PubMed  Google Scholar 

  • Milella M, Estrov Z, Kornblau SM, Carter BZ, Konopleva M, Tari A et al (2002) Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood 99:3461–3464

    CAS  PubMed  Google Scholar 

  • Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell 80:293–299

    CAS  PubMed  Google Scholar 

  • Momoi T (2006) Conformational diseases and ER stress-mediated cell death: apoptotic cell death and autophagic cell death. Curr Mol Med 6(1):111–118

    CAS  PubMed  Google Scholar 

  • Mullican S, Zhang S, Konopleva M, Ruvolo V, Andreeff M, Milbrandt J et al (2007) Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13(6):730–735

    CAS  PubMed  Google Scholar 

  • Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K et al (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16(11):1345–1355

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oakes SA, Scorrano L, Opferman JT, Bassik MC, Nishino M, Pozzan T et al (2005) Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc Natl Acad Sci U S A 102:105–110

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ozcan L, Tabas I (2012) Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 63:317–328

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al (2005) Bcl-2 antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell 122:927–939

    CAS  PubMed  Google Scholar 

  • Pellecchia M, Reed JC (2004) Inhibition of anti-apoptotic Bcl-2 family proteins by natural polyphenols: new avenues for cancer chemoprevention and chemotherapy. Curr Pharm Des 10:1387–1398

    CAS  PubMed  Google Scholar 

  • Penninger JM, Kroemer G (2003) Mitochondria, AIF and caspases–rivaling for cell death execution. Nat Cell Biol 5:97–99

    CAS  PubMed  Google Scholar 

  • Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B et al (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38(6):899–914

    CAS  PubMed  Google Scholar 

  • Puthalakath H, O’Reilly L, Gunn P, Lee L, Kelly P, Huntington N et al (2007) ER stress triggers apoptosis by activating BH3-only protein bim. Cell 129:1337–1349

    CAS  PubMed  Google Scholar 

  • Qian S, Wang W, Yang L, Huang HW (2008) Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proc Natl Acad Sci U S A 105(45):17379–17383

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rao RV, Bredesen DE (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol 16:653–662

    PubMed Central  CAS  PubMed  Google Scholar 

  • Reed JC (1996) Balancing cell life and death: bax, apoptosis, and breast cancer. J Clin Invest 97: 2403–2404

    PubMed Central  CAS  PubMed  Google Scholar 

  • Reed JC (1997) Double identity for proteins of the Bcl-2 family. Nature 387:773–776

    CAS  PubMed  Google Scholar 

  • Reed JC (2005) Pellecchia M. apoptosis-based therapies for hematological malignancies. Blood 106:408–418

    CAS  PubMed  Google Scholar 

  • Reed JC (2006) Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 13(8):1378–1386

    CAS  PubMed  Google Scholar 

  • Reed JC (2008) Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood 111(7):3322–3330

    PubMed Central  CAS  PubMed  Google Scholar 

  • Reed JC, Doctor KS, Godzik A (2004) The domains of apoptosis: a genomics perspective. Science STKE 239:RE9

    Google Scholar 

  • Reimers K, Choi CY, Bucan V, Vogt PM (2008) The Bax Inhibitor-1 (BI-1) Family in Apoptosis and Tumorigenesis. Curr Mol Med 8(2):148–156

    CAS  PubMed  Google Scholar 

  • Rochitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M et al (1999) Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the swiss group for clinical cancer research. Leukemia 13(9):1352–1358

    Google Scholar 

  • Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H et al (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64(17):5943–5947

    CAS  PubMed  Google Scholar 

  • Rong YP, Aromolaran AS, Bultynck G, Zhong F, Li X, McColl K et al (2008) Targeting Bcl-2-IP3 Receptor Interaction to Reverse Bcl-2’s Inhibition of Apoptotic Calcium Signals. Mol Cell 31(2):255–265

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sakaki K, Wu J, Kaufman RJ (2008) Protein Kinase C{theta} is required for autophagy in response to stress in the endoplasmic reticulum. J Biol Chem 283(22):15370–15380

    PubMed Central  CAS  PubMed  Google Scholar 

  • Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES et al (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429:75–79

    CAS  PubMed  Google Scholar 

  • Salvesen GS (2002) Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 9:3–5

    PubMed  Google Scholar 

  • Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410

    CAS  PubMed  Google Scholar 

  • Salvesen GS, Renatus M (2002) Apoptosome: the seven-spoked death machine. Develop Cell 2:256–257

    CAS  Google Scholar 

  • Sano R, Hou Y-CC, Hedvat M, Correa RG, Shu CW, Krajewska M et al (2012) Endoplasmic Reticulum Protein BI-1 regulates Ca2+ -mediated bioenergetics to promote autophagy Genes Dev 26(10):1041–1054

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schaich M, Illmer T, Seitz G, Mohr B, Schakel U, Beck JF et al (2001) The prognostic value of Bcl-XL gene expression for remission induction is influenced by cytogenetics in adult acute myeloid leukemia. Haematologica 86:470–477

    CAS  PubMed  Google Scholar 

  • Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487

    CAS  PubMed  Google Scholar 

  • Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K et al (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38(5):605–614

    CAS  PubMed  Google Scholar 

  • Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo D (1998) Involvement of microtubules in the regulation of Bcl-2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18:3509–3517

    PubMed Central  CAS  PubMed  Google Scholar 

  • Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ et al (2001) Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem 276(5):3149–3157

    CAS  PubMed  Google Scholar 

  • Tschopp J, Irmler M, Thome M (1998) Inhibition of Fas death signals by FLIPs. Curr Opin Immunol 10:552–558

    CAS  PubMed  Google Scholar 

  • Upton JP, Austgen K, Nishino M, Coakley KM, Hagen A, Han D et al (2008) Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress. Mol Cell Biol 28(12):3943–3951

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vicencio JM, Ortiz C, Criollo A, Jones AW, Kepp O, Galluzzi L et al (2009) The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 16(7):1006–1017

    CAS  PubMed  Google Scholar 

  • Vogler M, Dinsdale D, Dyer MJ, Cohen GM (2009) Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 16(3):360–367

    CAS  PubMed  Google Scholar 

  • Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Ann Rev Immunol 17:331–367

    CAS  Google Scholar 

  • Wang XZ, Ron D (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science 272:1347–1349

    CAS  PubMed  Google Scholar 

  • Wei Y, Sinha S, Levine B (2008) Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 4(7):949–951

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xu Q, Reed JC (1998) BAX inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1:337–346

    CAS  PubMed  Google Scholar 

  • Xu C, Bailly-Maitre B, Reed JC (2005) Endoplamic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xu C, Xu W, Palmer AE, Reed JC (2008) BI-1 regulates endoplasmic reticulum Ca2 + homeostasis downstream of Bcl-2 family proteins. J Biol Chem 283(17):11477–11484

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yamaguchi R, Lartigue L, Perkins G, Scott RT, Dixit A, Kushnareva Y et al (2008) Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell 31(4):557–569

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281(40):30299–30304

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zalckvar E, Berissi H, Eisenstein M, Kimchi A (2009) Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy 5(5):720–722

    CAS  PubMed  Google Scholar 

  • Zhao R, Follows GA, Beer PA, Scott LM, Huntly BJ, Green AR et al (2008) Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. N Engl J Med 359(26):2778–2789

    CAS  PubMed  Google Scholar 

  • Zhong Q, Gao W, Du F, Wang X (2005) Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121:1085–1095

    CAS  PubMed  Google Scholar 

  • Zou W, Yue P, Khuri FR, Sun SY (2008) Coupling of endoplasmic reticulum stress to CDDO-Me-induced up-regulation of death receptor 5 via a CHOP-dependent mechanism involving JNK activation. Cancer Res 68(18):7484–7492

    PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sanford Burnham Institute for Medical Research, 10901 North Torrey Pines Road, 92037, La Jolla, CA, USA

    John C. Reed

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  1. John C. Reed
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Correspondence to John C. Reed .

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Editors and Affiliations

  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Conclusions

Conclusions

Bcl-2 family proteins are intricately involved in the biology of AML. From pathogenesis to progression and resistance to therapy, Bcl-2 family proteins are inextricably linked to AML. The advent of experimental therapeutics targeting anti-apoptotic Bcl-2 family proteins (small molecules) and mRNA (antisense) creates hope that are more effective strategies for treating AML may be near.

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Reed, J. (2015). Roles of Apoptosis-Regulating Bcl-2 Family Genes in AML. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_3

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  • DOI: https://doi.org/10.1007/978-1-4939-1393-0_3

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