Targeted Therapeutic Approaches for AML

  • Robert J. Arceci
  • Donald Small


Acute myeloid leukemia comprises about 20% of the acute leukemias in children, but it is responsible for more than half of leukemic deaths due to leukemia. Compared to the tremendous success in the treatment of acute lymphocytic leukemia in the last three decades, resulting in more than 80% cure rate, improvements in AML therapy have been more limited with only about half of patients with AML being cured. Risk-adapted therapy has been the cornerstone of ALL therapy. One of the reasons for the success of this approach in ALL is that standard ALL induction and consolidation have been able to be intensified without causing significant morbidity and mortality. In contrast, the leukemic stem cell in most AML subtypes is inherently more drug resistant requiring significantly intensified courses of near myeloablative combinations of chemotherapeutic agents. This has resulted in a plateau in survival at approximately 50% along with significant morbidity and mortality.


Cytosine Arabinoside Gemtuzumab Ozogamicin Leukemic Stem Cell Core Binding Factor Farnesyl Transferase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ichikawa H, Tanabe K, Mizushima H, et al. Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukaemia. Br J Haematol. 2006;135:336–347.PubMedGoogle Scholar
  2. Jordan CT. The leukemic stem cell. Best Pract Res Clin Haematol. 2007;20:13–18.PubMedGoogle Scholar
  3. Barabe F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science. 2007;316:600–604.PubMedGoogle Scholar
  4. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5:738–743.PubMedGoogle Scholar
  5. Andersson A, Eden P, Lindgren D, et al. Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations. Leukemia. 2005;19:1042–1050.PubMedGoogle Scholar
  6. Andersson A, Olofsson T, Lindgren D, et al. Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. Proc Natl Acad Sci U S A. 2005;102:19069–19074.PubMedGoogle Scholar
  7. Ross ME, Mahfouz R, Onciu M, et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004;104:3679–3687.PubMedGoogle Scholar
  8. Oshima Y, Ueda M, Yamashita Y, et al. DNA microarray analysis of hematopoietic stem cell-like fractions from individuals with the M2 subtype of acute myeloid leukemia. Leukemia. 2003;17:1990–1997.PubMedGoogle Scholar
  9. Kiyoi H, Naoe T, Yokota S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11:1447–1452.Google Scholar
  10. Kiyoi H, Towatari M, Yokota S, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–1337.PubMedGoogle Scholar
  11. Meshinchi S, Alonzo TA, Gerbing R, Lange B, Radich JP. FLT3 internal tandem duplication is a prognostic factor for poor outcome in pediatric AML; a CCG-1961 study [abstract]. Blood. 2003;102:335a.Google Scholar
  12. Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94.PubMedGoogle Scholar
  13. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–2439.PubMedGoogle Scholar
  14. Schnittger S, Bacher U, Haferlach C, Kern W, Haferlach T. Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients. Leukemia. 2007;21:725–731.PubMedGoogle Scholar
  15. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107:1791–1799.PubMedGoogle Scholar
  16. Shimada A, Taki T, Tabuchi K, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107:1806–1809.PubMedGoogle Scholar
  17. Tse KF, Mukherjee G, Small D. Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia. 2000;14:1766–1776.PubMedGoogle Scholar
  18. Ning ZQ, Li J, Arceci RJ. Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells. Leuk Lymphoma. 2001;41:513–522.PubMedGoogle Scholar
  19. Ning ZQ, Li J, Arceci RJ. Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells. Blood. 2001;97:3559–3567.PubMedGoogle Scholar
  20. Ning ZQ, Li J, McGuinness M, Arceci RJ. STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity. Oncogene. 2001;20:4528–4536.PubMedGoogle Scholar
  21. Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005;106:673–680.PubMedGoogle Scholar
  22. Pollard JA, Alonzo TA, Gerbing RB, et al. FLT3 internal tandem duplication in CD34+/CD33− precursors predicts poor outcome in acute myeloid leukemia. Blood. 2006;108:2764–2769.PubMedGoogle Scholar
  23. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100:2393–2398.PubMedGoogle Scholar
  24. Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20:1217–1220.PubMedGoogle Scholar
  25. Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia. 2006;20:1368–1376.PubMedGoogle Scholar
  26. Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99:3885–3891.PubMedGoogle Scholar
  27. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104:1145–1150.PubMedGoogle Scholar
  28. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669–3676.PubMedGoogle Scholar
  29. DeAngelo DJ, Stone RM, Heaney ML, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006;108:3674–3681.PubMedGoogle Scholar
  30. Cools J, Stover EH, Boulton CL, et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. Cancer Cell. 2003;3:459–469.PubMedGoogle Scholar
  31. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60.PubMedGoogle Scholar
  32. Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006;108:3477–3483.PubMedGoogle Scholar
  33. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006;108:3262–3270.PubMedGoogle Scholar
  34. Levis M, Smith BD, Beran M, et al. A randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. Blood. 2005;106:403a.Google Scholar
  35. Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–47.PubMedGoogle Scholar
  36. Roberts KG, Odell AF, Byrnes EM, et al. Resistance to c-KIT kinase inhibitors conferred by V654A mutation. Mol Cancer Ther. 2007;6:1159–1166.PubMedGoogle Scholar
  37. Meshinchi S, Stirewalt DL, Alonzo TA, et al. Activating mutations of RTK/RAS signal transduction pathway in pediatric acute myeloid leukemia. Blood. 2003;102:1474–1479.PubMedGoogle Scholar
  38. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–932.PubMedGoogle Scholar
  39. Fernandez A, Sanguino A, Peng Z, et al. An anticancer c-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest. 2007;117:4044–4054.PubMedGoogle Scholar
  40. Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood. 2004;103:3644–3654.PubMedGoogle Scholar
  41. Ito K, Tominaga K, Suzuki T, Jinnai I, Bessho M. Successful treatment with imatinib mesylate in a case of minor BCR–ABL-positive acute myelogenous leukemia. Int J Hematol. 2005;81:242–245.PubMedGoogle Scholar
  42. Jentsch-Ullrich K, Pelz AF, Braun H, et al. Complete molecular remission in a patient with Philadelphia-chromosome positive acute myeloid leukemia after conventional therapy and imatinib. Haematologica. 2004;89:ECR15.Google Scholar
  43. Pompetti F, Spadano A, Sau A, et al. Long-term remission in BCR/ABL-positive AML-M6 patient treated with imatinib mesylate. Leuk Res. 2007;31:563–567.PubMedGoogle Scholar
  44. Heidel F, Cortes J, Rucker FG, et al. Results of a multicenter phase II trial for older patients with c-kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose Ara-C and imatinib. Cancer. 2007;109:907–914.PubMedGoogle Scholar
  45. Hizuka N, Sukegawa I, Takano K, et al. Characterization of insulin-like growth factor I receptors on human erythroleukemia cell line (K-562 cells). Endocrinol Jpn. 1987;34:81–88.PubMedGoogle Scholar
  46. Abe S, Funato T, Takahashi S, et al. Increased expression of insulin-like growth factor i is associated with Ara-C resistance in leukemia. Tohoku J Exp Med. 2006;209:217–228.PubMedGoogle Scholar
  47. Frostad S, Bruserud O. In vitro effects of insulin-like growth factor-1 (IGF-1) on proliferation and constitutive cytokine secretion by acute myelogenous leukemia blasts. Eur J Haematol. 1999;62:191–198.PubMedGoogle Scholar
  48. Cosaceanu D, Carapancea M, Alexandru O, et al. Comparison of three approaches for inhibiting insulin-like growth factor I receptor and their effects on NSCLC cell lines in vitro. Growth Factors. 2007;25:1–8.PubMedGoogle Scholar
  49. Jerome L, Alami N, Belanger S, et al. Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. Cancer Res. 2006;66:7245–7252.PubMedGoogle Scholar
  50. Perl AE, Carroll M. Exploiting signal transduction pathways in acute myelogenous leukemia. Curr Treat Options Oncol. 2007;8:265–276.PubMedGoogle Scholar
  51. Aguayo A. The role of angiogenesis in the biology and therapy of myelodysplastic syndromes. Curr Hematol Rep. 2004;3:184–191.PubMedGoogle Scholar
  52. Aguayo A, Estey E, Kantarjian H, et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999;94:3717–3721.PubMedGoogle Scholar
  53. Aguayo A, Giles F, Albitar M. Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk Lymphoma. 2003;44:213–222.PubMedGoogle Scholar
  54. Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood. 2000;95:309–313.PubMedGoogle Scholar
  55. Kessler T, Fehrmann F, Bieker R, Berdel WE, Mesters RM. Vascular endothelial growth factor and its receptor as drug targets in hematological malignancies. Curr Drug Targets. 2007;8:257–268.PubMedGoogle Scholar
  56. Schuch G, Machluf M, Bartsch G, Jr., et al. In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood. 2002;100:4622–4628.PubMedGoogle Scholar
  57. Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood. 2002;99:2179–2184.PubMedGoogle Scholar
  58. Liersch R, Schliemann C, Bieker R, et al. Expression of VEGF-C and its receptor VEGFR-3 in the bone marrow of patients with acute myeloid leukaemia. Leuk Res. 2008;32:954–961.PubMedGoogle Scholar
  59. Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed and ­refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004;10:3577–3585.PubMedGoogle Scholar
  60. Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood. 2003;102:2763–2767.PubMedGoogle Scholar
  61. Maris JM, Courtright J, Houghton PJ, et al. Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50:581–587.PubMedGoogle Scholar
  62. Piloto O, Wright M, Brown P, Kim KT, Levis M, Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood. 2007;109:1643–1652.PubMedGoogle Scholar
  63. Farr C, Gill R, Katz F, Gibbons B, Marshall CJ. Analysis of RAS gene mutations in childhood myeloid leukaemia. Br J Haematol. 1991;77:323–327.PubMedGoogle Scholar
  64. Loh ML, Vattikuti S, Schubbert S, et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood. 2004;103:2325–2331.PubMedGoogle Scholar
  65. Karp JE. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. Semin Hematol. 2001;38:16–23.PubMedGoogle Scholar
  66. Karp JE. Farnesyl transferase inhibition in hematologic malignancies. J Natl Compr Canc Netw. 2005;3 Suppl 1:S37–S40.PubMedGoogle Scholar
  67. Emanuel PD, Snyder RC, Wiley T, Gopurala B, Castleberry RP. Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors. Blood. 2000;95:639–645.PubMedGoogle Scholar
  68. Gotlib J. Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Curr Hematol Rep. 2005;4:77–84.PubMedGoogle Scholar
  69. Harousseau JL, Lancet JE, Reiffers J, et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood. 2007;109:5151–5156.PubMedGoogle Scholar
  70. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109:1387–1394.PubMedGoogle Scholar
  71. Milella M, Estrov Z, Kornblau SM, et al. Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood. 2002;99:3461–3464.PubMedGoogle Scholar
  72. Milella M, Kornblau SM, Andreeff M. The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies. Rev Clin Exp Hematol. 2003;7:160–190.PubMedGoogle Scholar
  73. Milella M, Kornblau SM, Estrov Z, et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest. 2001;108:851–859.PubMedGoogle Scholar
  74. James JA, Smith MA, Court EL, et al. An investigation of the effects of the MEK inhibitor U0126 on apoptosis in acute leukemia. Hematol J. 2003;4:427–432.PubMedGoogle Scholar
  75. Tong FK, Chow S, Hedley D. Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells. Cytometry B Clin Cytom. 2006;70:107–114.PubMedGoogle Scholar
  76. Weisberg E, Banerji L, Wright RD, et al. Potentiation of anti-leukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR–ABL- and mutant FLT3-expressing cells. Blood. 2008.Google Scholar
  77. Tamburini J, Chapuis N, Bardet V, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111:379–382.PubMedGoogle Scholar
  78. Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003;102:972–980.PubMedGoogle Scholar
  79. Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood. 2005;106:4261–4268.PubMedGoogle Scholar
  80. Recher C, Beyne-Rauzy O, Demur C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105:2527–2534.PubMedGoogle Scholar
  81. Min YH, Eom JI, Cheong JW, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 2003;17:995–997.PubMedGoogle Scholar
  82. Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12:5165–5173.PubMedGoogle Scholar
  83. Baer MR, George SL, Dodge RK, et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002;100:1224–1232.PubMedGoogle Scholar
  84. Leith CP, Chen IM, Kopecky KJ, et al. Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR−/efflux+ and MDR1+/efflux− cases. Blood. 1995;86:2329–2342.PubMedGoogle Scholar
  85. Leith CP, Kopecky KJ, Chen IM, et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood. 1999;94:1086–1099.PubMedGoogle Scholar
  86. Willman CL. Immunophenotyping and cytogenetics in older adults with acute myeloid leukemia: significance of expression of the multidrug resistance gene-1 (MDR1). Leukemia. 1996;10 Suppl 1:S33–S35.PubMedGoogle Scholar
  87. Willman CL. The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the Southwest Oncology Group Leukemia Research Program. Semin Hematol. 1997;34:25–33.PubMedGoogle Scholar
  88. Sievers EL, Smith FO, Woods WG, et al. Cell surface expression of the multidrug resistance P-glycoprotein (P-170) as detected by monoclonal antibody MRK-16 in pediatric acute myeloid leukemia fails to define a poor prognostic group: a report from the Childrens Cancer Group. Leukemia. 1995;9:2042–2048.PubMedGoogle Scholar
  89. List AF, Spier C, Greer J, et al. Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. J Clin Oncol. 1993;11:1652–1660.PubMedGoogle Scholar
  90. Dahl GV, Lacayo NJ, Brophy N, et al. Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia. J Clin Oncol. 2000;18:1867–1875.PubMedGoogle Scholar
  91. Greenberg PL, Lee SJ, Advani R, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004;22:1078–1086.PubMedGoogle Scholar
  92. List AF, Kopecky KJ, Willman CL, et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2001;98:3212–3220.PubMedGoogle Scholar
  93. Becton D, Dahl GV, Ravindranath Y, et al. Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood. 2006;107:1315–1324.PubMedGoogle Scholar
  94. Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood. 2005;106:1183–1188.PubMedGoogle Scholar
  95. Linenberger ML, Hong T, Flowers D, et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood. 2001;98:988–994.PubMedGoogle Scholar
  96. Marcucci G, Byrd JC, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003;101:425–432.PubMedGoogle Scholar
  97. Marcucci G, Stock W, Dai G, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol. 2005;23:3404–3411.PubMedGoogle Scholar
  98. Moore J, Seiter K, Kolitz J, et al. A phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse. Leuk Res. 2006;30:777–783.PubMedGoogle Scholar
  99. Zavrski I, Jakob C, Kaiser M, Fleissner C, Heider U, Sezer O. Molecular and clinical aspects of proteasome inhibition in the treatment of cancer. Recent Results Cancer Res. 2007;176:165–176.PubMedGoogle Scholar
  100. Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98:2301–2307.PubMedGoogle Scholar
  101. Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A. 2002;99:16220–16225.PubMedGoogle Scholar
  102. Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. 2007;110:4427–4435.PubMedGoogle Scholar
  103. Pigneux A, Mahon FX, Moreau-Gaudry F, et al. Proteasome inhibition specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins. Cancer Biol Ther. 2007;6:603–611.PubMedGoogle Scholar
  104. Holliday R. Epigenetics: a historical overview. Epigenetics. 2006;1:76–80.PubMedGoogle Scholar
  105. Wood A, Schneider J, Shilatifard A. Cross-talking histones: implications for the regulation of gene expression and DNA repair. Biochem Cell Biol. 2005;83:460–467.PubMedGoogle Scholar
  106. Nie Z, Yan Z, Chen EH, et al. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Mol Cell Biol. 2003;23:2942–2952.PubMedGoogle Scholar
  107. Preisler HD, Li B, Chen H, et al. P15INK4B gene methylation and expression in normal, myelodysplastic, and acute myelogenous leukemia cells and in the marrow cells of cured lymphoma patients. Leukemia. 2001;15:1589–1595.PubMedGoogle Scholar
  108. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 1997;57:837–841.PubMedGoogle Scholar
  109. Seedhouse CH, Das-Gupta EP, Russell NH. Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia. 2003;17:83–88.PubMedGoogle Scholar
  110. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–681.PubMedGoogle Scholar
  111. Ting AH, McGarvey KM, Baylin SB. The cancer epigenome – components and functional correlates. Genes Dev. 2006;20:3215–3231.PubMedGoogle Scholar
  112. So CW, Karsunky H, Wong P, Weissman IL, Cleary ML. Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9. Blood. 2004;103:3192–3199.PubMedGoogle Scholar
  113. So CW, Lin M, Ayton PM, Chen EH, Cleary ML. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell. 2003;4:99–110.PubMedGoogle Scholar
  114. Ghoshal K, Bai S. DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007;43:395–422.Google Scholar
  115. Santini V, Gozzini A, Ferrari G. Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr Drug Metab. 2007;8:383–393.PubMedGoogle Scholar
  116. Garcia-Manero G, Yang AS, Jagasia M. Evaluating new treatment options for MDS. Clin Adv Hematol Oncol. 2007;5:1–9Google Scholar
  117. Gattermann N, Kundgen A, Germing U. Treatment of patients with high-risk myelodysplastic syndromes. Cancer Treat Rev. 2007;33 Suppl 1:S64–S68.Google Scholar
  118. Plimack ER, Kantarjian HM, Issa JP. Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma. 2007;48:1472–1481.PubMedGoogle Scholar
  119. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005;10:176–182.PubMedGoogle Scholar
  120. Silverman LR. Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8–14.PubMedGoogle Scholar
  121. Griffiths EA, Gore SD. DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol. 2008;45:23–30.PubMedGoogle Scholar
  122. Qin T, Youssef EM, Jelinek J, et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res. 2007;13:4225–4232.PubMedGoogle Scholar
  123. Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–6369.PubMedGoogle Scholar
  124. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279.PubMedGoogle Scholar
  125. Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640.PubMedGoogle Scholar
  126. Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–2308.PubMedGoogle Scholar
  127. Kantarjian HM, O’Brien S, Huang X, et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer. 2007;109:1133–1137.PubMedGoogle Scholar
  128. Li Q, Kopecky KJ, Mohan A, et al. Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia. Clin Cancer Res. 1999;5:1077–1084.PubMedGoogle Scholar
  129. Larson RA, Sievers EL, Stadtmauer EA, et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104:1442–1452.PubMedGoogle Scholar
  130. Aplenc R, Alonzo T, Gerbing A, Robert B, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia. J Clin Oncol. 2008;26:2390–3295.PubMedGoogle Scholar
  131. Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood. 2003;102:4277–4283.PubMedGoogle Scholar
  132. Burnett AK, Kell WJ, Goldstone AH, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 trial. Blood. 2006;108:8a.Google Scholar
  133. Taussig DC, Pearce DJ, Simpson C, et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood. 2005;106:4086–4092.PubMedGoogle Scholar
  134. van Rhenen A, van Dongen GA, Kelder A, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007;110:2659–2666.PubMedGoogle Scholar
  135. Arceci RJ. The potential for antitumor vaccination in acute myelogenous leukemia. J Mol Med. 1998;76:80–93.PubMedGoogle Scholar
  136. Dunussi-Joannopoulos K, Dranoff G, Weinstein HJ, Ferrara JL, Bierer BE, Croop JM. Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines. Blood. 1998;91:222–230.PubMedGoogle Scholar
  137. Dunussi-Joannopoulos K, Krenger W, Weinstein HJ, Ferrara JL, Croop JM. CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment. Blood. 1997;89:2915–2924.PubMedGoogle Scholar
  138. Dunussi-Joannopoulos K, Weinstein HJ, Nickerson PW, et al. Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML. Blood. 1996;87:2938–2946.PubMedGoogle Scholar
  139. Cheuk AT, Guinn BA. Immunotherapy of acute myeloid leukaemia: development of a whole cell vaccine. Front Biosci. 2008;13:2022–2029.PubMedGoogle Scholar
  140. Chan L, Hardwick N, Darling D, et al. IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. Mol Ther. 2005;11:120–131.PubMedGoogle Scholar
  141. Houtenbos I, Westers TM, Ossenkoppele GJ, van de Loosdrecht AA. Feasibility of clinical dendritic cell vaccination in acute myeloid leukemia. Immunobiology. 2006;211:677–685.PubMedGoogle Scholar
  142. Greiner J, Li L, Ringhoffer M, et al. Identification and characterization of epitopes of the receptor for hyaluronic acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-A2-positive patients with acute myeloid leukemia. Blood. 2005;106:938–945.PubMedGoogle Scholar
  143. Greiner J, Ringhoffer M, Taniguchi M, et al. mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer. 2004;108:704–711.PubMedGoogle Scholar
  144. Gaiger A, Reese V, Disis ML, Cheever MA. Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood. 2000;96:1480–1489.PubMedGoogle Scholar
  145. Greiner J, Dohner H, Schmitt M. Cancer vaccines for patients with acute myeloid leukemia – definition of leukemia-associated antigens and current clinical protocols targeting these antigens. Haematologica. 2006;91:1653–1661.PubMedGoogle Scholar
  146. Lange B, Smith FO, Feusner J, et al. Outcomes in CC-2961: a Children’s Cancer Group Phase 3 Trial for untreated pediatric acute myeloid leukemia (AML). Blood. 2008;111:1044–1053.PubMedGoogle Scholar
  147. Arceci RJ, Cripe TP. Emerging cancer-targeted therapies. Pediatr Clin North Am. 2002;49:1339–1368, vii–viiiPubMedGoogle Scholar
  148. Doepfner KT, Boller D, Arcaro A. Targeting receptor tyrosine kinase signaling in acute myeloid leukemia. Crit Rev Oncol Hematol. 2007;63:215–230.PubMedGoogle Scholar
  149. Poland KS, Shardy DL, Azim M, et al. Overexpression of ZNF 342 by juxtaposition with MPO Promoter/enhancer in the novel translocation t(17;19) (q23; q13.32) in pediatric acute myeloid leukemia and analysis of ZNF 342 expression in leukemia. Genes Chromosomes Cancer. 2009;48:480–489.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Pediatric OncologyJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations