REFERENCES
2. Löwenberg B, Ossenkoppele GJ, van Putten W, et al; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON), German AML Study Group (AMLSG), Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235-48.
3. Prébet T, Boissel N, Reutenauer S, et al; Acute Leukemia French Association, Groupe Ouest-Est des leucémies et autres maladies du sang (GOELAMS), Core Binding Factor Acute Myeloid Leukemia (CBF AML) intergroup. Acute myeloid leukemia with translocation (8;21) or inversion (16) in elderly patients treated with conventional chemotherapy: a collaborative study of the French CBF-AML intergroup. J Clin Oncol 2009;27:4747-53.
4. Wahlin A, Markevärn B, Golovleva I, Nilsson M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001;115:25-33.
5. Farag SS, Archer KJ, Mrózek K, et al; Cancer and Leukemia Group B 8461. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood 2006;108:63-73.
6. Grimwade D, Walker H, Harrison G, et al; Medical Research Council Adult Leukemia Working Party. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1312-20.
7. Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 2007;25:1908-15.
8. Krug U, Büchner T, Berdel WE, Müller-Tidow C. The treatment of elderly patients with acute myeloid leukemia. Dtsch Arztebl Int 2011;108:863-70.
9. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant 2015;21:559-64.
10. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 2013;121:4854-60.
11. Grimwade D, Hills RK, Moorman AV, et al; National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-65.
12. Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol 2017;35:934-46.
13. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 2010;116:4422-9.
14. Kantarjian H, O’brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006;106:1090-8.
15. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with Ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:2386-98.
16. Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-
17. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454-64.
18. Bose P, Vachhani P, Cortes JE. Treatment of relapsed/refractory acute myeloid leukemia. Curr Treat Options Oncol 2017;18:17.
19. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7-17.
20. Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II Study. J Clin Oncol 2019;37:1277-84.
21. Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012;120:4840-5.
22. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood 2015;126:291-9.
23. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2010;28:556-61.
24. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012;30:2670-7.
25. Al-Ali HK, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012;53:110-7.
26. Cidado J, Boiko S, Proia T, et al. AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clin Cancer Res 2020;26:922-34.
27. Richard-Carpentier G, DiNardo CD. Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Ther Adv Hematol 2019;10:2040620719882822.
28. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020;383:617-29.
29. Braun T, Itzykson R, Renneville A, et al; Groupe Francophone des Myélodysplasies. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011;118:3824-31.
30. Pleyer L, Germing U, Sperr WR, et al. Azacitidine in CMML: matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival. Leuk Res 2014;38:475-83.
31. Sekeres MA, Othus M, List AF, et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: north american intergroup study SWOG S1117. J Clin Oncol 2017;35:2745-53.
32. Fenaux P, Mufti GJ, Hellstrom-lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.
33. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol 2018;93:401-7.
34. Sorm F, Pískala A, Cihák A, Veselý J. 5-Azacytidine, a new, highly effective cancerostatic. Experientia 1964;20:202-3.
35. Gu X, Tohme R, Tomlinson B, et al. Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network. Leukemia 2020; doi: 10.1038/s41375-020-1003-x.
36. Qin T, Jelinek J, Si J, Shu J, Issa JP. Mechanisms of resistance to 5-aza-2’-deoxycytidine in human cancer cell lines. Blood 2009;113:659-67.
37. Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 2010;5:e9001.
38. Leone G, D’Alò F, Zardo G, Voso MT, Nervi C. Epigenetic treatment of myelodysplastic syndromes and acute myeloid leukemias. Curr Med Chem 2008;15:1274-87.
39. Bird AP, Southern EM. Use of restriction enzymes to study eukaryotic DNA methylation. J Mol Biol 1978;118:27-47.
40. McGhee JD, Ginder GD. Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature 1979;280:419-20.
41. Desrosiers RC, Mulder C, Fleckenstein B. Methylation of Herpesvirus saimiri DNA in lymphoid tumor cell lines. Proc Natl Acad Sci U S A 1979;76:3839-43.
42. Constantinides PG, Taylor SM, Jones PA. Phenotypic conversion of cultured mouse embryo cells by aza pyrimidine nucleosides. Dev Biol 1978;66:57-71.
43. Taylor SM, Jones PA. Multiple new phenotypes induced in and 3T3 cells treated with 5-azacytidine. Cell 1979;17:771-9.
44. Constantinides PG, Jones PA, Gevers W. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature 1977;267:364-6.
45. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980;20:85-93.
46. Veselý J. Mode of action and effects of 5-azacytidine and of its derivatives in eukaryotic cells. Pharmacol Therap 1985;28:227-35.
47. Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 2008;123:8-13.
48. Kuykendall JR. 5-azacytidine and decitabine monotherapies of myelodysplastic disorders. Ann Pharmacother 2005;39:1700-9.
49. Lee TT, Karon MR. Inhibition of protein synthesis in 5-azacytidine-treated HeLa cells. Biochem Pharmacol 1976;25:1737-42.
50. Lu LJ, Randerath K. Mechanism of 5-azacytidine-induced transfer rna cytosine-5-methyltransferase deficiency. Cancer Res 1980;40:2701-5.
51. Schaefer M, Hagemann S, Hanna K, Lyko F. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res 2009;69:8127-32.
52. Taylor SM, Jones PA. Mechanism of action of eukaryotic DNA methyltransferase. J Mol Biol 1982;162:679-92.
53. Santi DV, Norment A, Garrett CE. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci U S A 1984;81:6993-7.
54. Christman JK, Schneiderman N, Acs G. Formation of highly stable complexes between 5-azacytosine-substituted DNA and specific non-histone nuclear proteins. Implications for 5-azacytidine-mediated effects on DNA methylation and gene expression. J Biol Chem 1985;260:4059-68.
55. Ferguson AT, Vertino PM, Spitzner JR, et al. Role of estrogen receptor gene demethylation and DNA methyltransferase.DNA adduct formation in 5-aza-2’deoxycytidine-induced cytotoxicity in human breast cancer cells. J Biol Chem 1997;272:32260-6.
56. Oka M, Meacham AM, Hamazaki T, Rodić N, Chang LJ, Terada N. De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2’-deoxycytidine. Oncogene 2005;24:3091-9.
57. Copeland RA, Olhava EJ, Scott MP. Targeting epigenetic enzymes for drug discovery. Curr Opin Chem Biol 2010;14:505-10.
58. Champion C, Guianvarc’h D, Sénamaud-Beaufort C, et al. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One 2010;5:e12388.
59. Chen L, MacMillan AM, Chang W, et al. Direct identification of the active-site nucleophile in a DNA (cytosine-5)-methyltransferase. Biochemistry 1991;30:11018-25.
60. Wilson VL, Jones PA, Momparler RL. Inhibition of DNA methylation in l1210 leukemic cells by 5-aza-2’-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res 1983;43:3493-6.
61. Bender CM, Zingg JM, Jones PA. DNA methylation as a target for drug design. Pharm Res 1998;15:175-87.
62. Muvarak NE, Chowdhury K, Xia L, et al. Enhancing the cytotoxic effects of PARP inhibitors with DNA demethylating agents - a potential therapy for cancer. Cancer Cell 2016;30:637-50.
63. Jüttermann R, Li E, Jaenisch R. Toxicity of 5-aza-2’-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci U S A 1994;91:11797-801.
64. Stingele J, Bellelli R, Boulton SJ. Mechanisms of DNA-protein crosslink repair. Nat Rev Mol Cell Biol 2017;18:563-73.
65. Veselý J, Cihák A, Sorm F. Characteristics of mouse leukemic cells resistant to 5-azacytidine and 5-aza-2’-deoxycytidine. Cancer Res 1968;28:1995-2000.
66. Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H. Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A 2005;102:8905-9.
67. Vispé S, Deroide A, Davoine E, et al. Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2’-deoxycytidine in human leukemic KG1 cells. Oncotarget 2015;6:15265-82.
68. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant
69. Savona MR, Odenike O, Amrein PC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol 2019;6:e194-203.
70. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 2020;136:674-83.
71. Roboz GJ, Montesinos P, Selleslag D, et al. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncol 2016;12:293-302.
72. Wei AH, Döhner H, Pocock C, et al. The quazar aml-001 maintenance trial: results of a phase iii international, randomized, double-blind, placebo-controlled study of cc-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (aml) in first remission. American Society of Hematology Washington, DC; 2019.
74. Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-AZA-2ʹ-deoxycytidine in patients with acute leukemia. Pharmacol Therap 1985;30:277-86.
75. Rivard GE, Momparler RL, Demers J, et al. Phase I study on 5-aza-2ʹ-deoxycytidine in children with acute leukemia. Leuk Res 1981;5:453-62.
76. Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000;18:956-62.
77. Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-Aza-2’-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 1997;11:1-5.
78. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006;106:1794-803.
79. Lübbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011;29:1987-96.
80. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20:2429-40.
81. Karon M, Sieger L, Leimbrock S, et al. 5-azacytidine: a new active agent for the treatment of acute leukemia. Blood 1973;42:359-65.
82. Saiki JH, Bodey GP, Hewlett JS, et al. Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia: a southwest oncology group study. Cancer 1981;47:1739-42.
83. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-9.
84. Harris NL, Jaffe ES, Diebold J, et al. The world health organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting--Airlie House, Virginia, November, 1997. Hematol J 2000;1:53-66.
85. Silverman LR, McKenzie DR, Peterson BL, et al; Cancer and Leukemia Group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006;24:3895-903.
86. Pleyer L, Burgstaller S, Girschikofsky M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol 2014;93:1825-38.
87. Thépot S, Itzykson R, Seegers V, et al; Groupe Francophone des Myélodysplasies (GFM), Acute Leukemia French Association (ALFA); Groupe Ouest-Est des Leucémies Aiguës; Maladies du Sang (GOELAMS). Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. Am J Hematol 2014;89:410-6.
88. Hummel-Eisenbeiss J, Hascher A, Hals PA, et al. The role of human equilibrative nucleoside transporter 1 on the cellular transport of the DNA methyltransferase inhibitors 5-azacytidine and CP-4200 in human leukemia cells. Mol Pharmacol 2013;84:438-50.
89. Wu P, Geng S, Weng J, et al. The hENT1 and DCK genes underlie the decitabine response in patients with myelodysplastic syndrome. Leuk Res 2015;39:216-20.
90. Brueckner B, Rius M, Markelova MR, et al. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol Cancer Ther 2010;9:1256-64.
91. Camiener GW, Smith CG. Studies of the enzymatic deamination of cytosine arabinoside-I. Biochem Pharmacol 1965;14:1405-16.
92. Zauri M, Berridge G, Thézénas ML, et al. CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature 2015;524:114-8.
93. Eliopoulos N, Cournoyer D, Momparler RL. Drug resistance to 5-aza-2’-deoxycytidine, 2’,2’-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol 1998;42:373-8.
94. Beauséjour CM, Eliopoulos N, Momparler L, Le NL, Momparler RL. Selection of drug-resistant transduced cells with cytosine nucleoside analogs using the human cytidine deaminase gene. Cancer Gene Ther 2001;8:669-76.
95. Valencia A, Masala E, Rossi A, et al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia 2014;28:621-8.
96. Qin T, Castoro R, El Ahdab S, et al. Mechanisms of resistance to decitabine in the myelodysplastic syndrome. PLoS One 2011;6:e23372.
97. Gruber E, Franich RL, Shortt J, Johnstone RW, Kats LM. Distinct and overlapping mechanisms of resistance to azacytidine and guadecitabine in acute myeloid leukemia. Leukemia 2020;34:3388-92.
98. Grant S, Bhalla K, Gleyzer M. Interaction of deoxycytidine and deoxycytidine analogs in normal and leukemic human myeloid progenitor cells. Leukemia Research 1986;10:1139-46.
99. Grant S, Bhalla K, Gleyzer M. Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis. Cancer Res 1984;44:5505-10.
100. Itzykson R, Kosmider O, Cluzeau T, et al; Groupe Francophone des Myelodysplasies (GFM). Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 2011;25:1147-52.
101. Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014;124:2705-12.
102. Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 2014;28:78-87.
103. Cedena MT, Rapado I, Santos-lozano A, et al. Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes. Oncotarget 2017;8:106948-61.
104. Coombs CC, Sallman DA, Devlin SM, et al. Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. Haematologica 2016;101:e457-60.
105. Ali A, Penneroux J, Dal Bello R Jr, et al. Granulomonocytic progenitors are key target cells of azacytidine in higher risk myelodysplastic syndromes and acute myeloid leukemia. Leukemia 2018;32:1856-60.
106. Treppendahl MB, Kristensen LS, Grønbæk K. Predicting response to epigenetic therapy. J Clin Invest 2014;124:47-55.
107. Li LH, Olin EJ, Buskirk HH, Reineke LM. Cytotoxicity and mode of action of 5-azacytidine on l1210 leukemia. Cancer Res 1970;30:2760-9.
108. Cheng JX, Chen L, Li Y, et al. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat Commun 2018;9:1163.
109. Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates and functions during apoptosis. Ann Rev Biochem 1999;68:383-424.
110. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 2008;9:231-41.
111. Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J 2011;30:3667-83.
112. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014;15:49-63.
113. Moldoveanu T, Follis AV, Kriwacki RW, Green DR. Many players in BCL-2 family affairs. Trends Biochem Sci 2014;39:101-11.
114. Llambi F, Moldoveanu T, Tait SW, et al. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 2011;44:517-31.
115. Andreeff M, Jiang S, Zhang X, et al. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia 1999;13:1881-92.
116. Venditti A, Del Poeta G, Maurillo L, et al. Combined analysis of bcl-2 and mdr1 proteins in 256 cases of acute myeloid leukemia. Haematologica 2004;89:934-9.
117. Delbridge AR, Grabow S, Strasser A, Vaux DL. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 2016;16:99-109.
118. Cory S, Roberts AW, Colman PM, Adams JM. Targeting BCL-2-like Proteins to Kill Cancer Cells. Trends Cancer 2016;2:443-60.
119. Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 2019;20:175-93.
120. Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell 2018;34:879-91.
121. Tse C, Shoemaker AR, Adickes J, et al. Abt-263: a potent and orally bioavailable bcl-2 family inhibitor. Cancer Res 2008;68:3421-8.
122. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016;17:768-78.
123. Wilson WH, O’connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010;11:1149-59.
124. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 2012;30:488-96.
125. Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell 2007;128:1173-86.
126. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202-8.
127. Vogler M, Dinsdale D, Dyer MJ, Cohen GM. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol 2013;163:139-42.
128. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311-22.
129. Roberts AW, Huang D. Targeting BCL2 With BH3 mimetics: basic science and clinical application of venetoclax in chronic lymphocytic leukemia and related B cell malignancies. Clin Pharmacol Ther 2017;101:89-98.
130. Pham TD, Pham PQ, Li J, Letai AG, Wallace DC, Burke PJ. Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization. Sci Rep 2016;6:35907.
131. Lucantoni F, Düssmann H, Llorente-Folch I, Prehn JHM. BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose. Oncotarget 2018;9:26046-63.
132. Chen X, Glytsou C, Zhou H, et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov 2019;9:890-909.
133. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. Bcl-2 gene hypomethylation and high-level expression in b-cell chronic lymphocytic leukemia. Blood 1993;82:1820-8.
134. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99:15524-9.
135. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 2005;102:13944-9.
136. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 2016;127:3215-24.
137. Huemer F, Melchardt T, Jansko B, et al. Durable remissions with venetoclax monotherapy in secondary AML refractory to hypomethylating agents and high expression of BCL-2 and/or BIM. Eur J Haematol 2019;102:437-41.
138. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 2016;6:1106-17.
139. Tausch E, Close W, Dolnik A, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 2019;104:e434-7.
140. Birkinshaw RW, Gong JN, Luo CS, et al. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun 2019;10:2385.
141. Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov 2019;9:342-53.
142. Anderson MA, Tam C, Lew TE, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017;129:3362-70.
143. Tessoulin B, Papin A, Gomez-Bougie P, et al. BCL2-family dysregulation in B-cell malignancies: from gene expression regulation to a targeted therapy biomarker. Front Oncol 2018;8:645.
144. Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica 2015;100:e302-6.
145. Guièze R, Liu VM, Rosebrock D, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 2019;36:369-84.e13.
146. Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis 2015;6:e1593.
148. Mazumder S, Choudhary GS, Al-Harbi S, Almasan A. Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells. Cancer Res 2012;72:3069-79.
149. Luedtke DA, Niu X, Pan Y, et al. Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct Target Ther 2017;2:17012.
150. Niu X, Zhao J, Ma J, et al. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res 2016;22:4440-51.
151. Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of Resistance to ABT-199 in acute myeloid leukemia. Sci Rep 2016;6:27696.
152. Li Z, He S, Look AT. The MCL1-specific inhibitor S63845 acts synergistically with venetoclax/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells. Leukemia 2019;33:262-6.
153. Weiss J, Peifer M, Herling CD, Frenzel LP, Hallek M. Acquisition of the recurrent Gly101Val mutation in
154. Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A 2013;110:18250-5.
155. Nechiporuk T, Kurtz SE, Nikolova O, et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov 2019;9:910-25.
156. Sharon D, Cathelin S, Mirali S, et al. Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response. Sci Transl Med 2019;11:eaax2863.
157. Jin S, Cojocari D, Purkal JJ, et al. 5-Azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis. Clin Cancer Res 2020;26:3371-83.
158. Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol 2020;95:623-9.
159. Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol 2018:E202-5.
160. Kim E, Ilagan JO, Liang Y, et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on Exon recognition. Cancer Cell 2015;27:617-30.
161. Bogenberger JM, Kornblau SM, Pierceall WE, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia 2014;28:1657-65.
162. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014;4:362-75.
163. Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma 2015;56:226-9.
164. Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol 2012;91:1861-70.
165. Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med 2018;24:1859-66.
166. Jilg S, Hauch RT, Kauschinger J, et al. Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose. Exp Hematol Oncol 2019;8:9.
167. Pei S, Pollyea DA, Gustafson A, et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov 2020;10:536-51.
168. DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 2020;135:791-803.
169. Maiti A, Rausch CR, Cortes JE, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica 2020; doi: 10.3324/haematol.2020.252569.
170. Pievani A, Biondi M, Tomasoni C, Biondi A, Serafini M. Location first: targeting acute myeloid leukemia within its niche. J Clin Med 2020;9:1513.
171. Jacamo R, Chen Y, Wang Z, et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood 2014;123:2691-702.
172. Matsunaga T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003;9:1158-65.