Molecularly Targeted Therapy for Infant ALL

  • Patrick A. Brown
  • Carolyn A. Felix


Rational combinations of molecularly targeted agents with synergistic conventional cytotoxic chemotherapeutic agents or, ultimately, with one another are urgently needed for infants with acute leukemia. Leukemia is the commonest malignancy during infancy, comprises 2.5 to 5% of ALL and 6 to 14% of AML in pediatrics overall, (Gurney et al. 1999; Smith et al. 1999a; Pui et al. 1995; SEER Cancer Statistics Review 1975–2006) and represents a special leukemia subtype characterized by MLL (Mixed Lineage Leukemia) gene translocations. MLL translocations with heterogeneous partner genes, of which there are >60, (Meyer et al. 2009) are the primary molecular aberrations in infant ALL and infant AML alike; approximately 75 to 80% of infant ALL cases and myelomonocytic/monoblastic AML feature MLL translocations (Pui et al. 1995; Rubnitz et al. 1994; Robinson et al. 2009). Within infant ALL cases with MLL translocations, 70 and 13% involve the AF4 (ALL-1 fused gene from chromosome 4) or ENL (Eleven-nineteen leukemia) partner genes, respectively, (Pui et al. 2003) whereas the partner genes in AML are more diverse. In one recent infant ALL treatment study, these more common partner genes were associated with only approximately 30% 5-year event free survival, with a poorer outcome associated with the CD10 immunophenotype and younger age at diagnosis (Hilden et al. 2006).


Gemtuzumab Ozogamicin FLT3 Inhibitor FLT3 Expression Infant Leukemia FLT3 Tyrosine Kinase Inhibition 
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.



The work is supported by Leukemia & Lymphoma Society SCOR 7372-07.


  1. Gurney JG, Smith MA, Ross JA. Cancer among infants. In: Ries LAG, Smith MA, Gurney JG, et al., eds. Cancer Incidence and Survival among children and adolescents: United States SEER program 1975–1995. Bethesda, MD: National Cancer Institute, SEER Program. NIH; 1999.Google Scholar
  2. Smith MA, Gloeckler-Ries LA, Gurney JG, Ross JA. Leukemia. In: Ries LAG, Smith MA, Gurney JG, et al., eds. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute, SEER Program, NIH; 1999.Google Scholar
  3. Pui CH, Kane JR, Crist WM. Biology and treatment of infant leukemias. Leukemia. 1995;9:762–769.PubMedGoogle Scholar
  4. SEER Cancer Statistics Review, 1975–2006; Scholar
  5. Meyer C, Kowarz E, Hofmann J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia. 2009.Google Scholar
  6. Rubnitz JE, Link MP, Shuster JJ, et al. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1994;84:570–573.PubMedGoogle Scholar
  7. Pui CH, Chessells JM, Camitta B, et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia. 2003;17:700–706.PubMedCrossRefGoogle Scholar
  8. Robinson BW, Devidas M, Carroll AJ, et al. Specific MLL partner genes in infant acute lym-phoblastic leukemia (ALL) associated with outcome are linked to age and white blood cell count (WBC) at diagnosis: A report on the Children’s Oncology Group (COG) P9407 trial. Blood (ASH Annual Meeting Abstracts) 2009;114(22):907.Google Scholar
  9. Hilden JM, Dinndorf PA, Meerbaum SO, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood. 2006;108:441–451.PubMedCrossRefGoogle Scholar
  10. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114:2489–2496.PubMedCrossRefGoogle Scholar
  11. Felix CA, Kolaris CP, Osheroff N. Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst). 2006;5:1093–1108.CrossRefGoogle Scholar
  12. Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol. 1999;17:569–577.PubMedGoogle Scholar
  13. Liedtke M, Cleary ML. Therapeutic targeting of MLL. Blood. 2009.Google Scholar
  14. Ziemin-van der Poel S, McCabe NR, Gill HJ, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci USA. 1991;88:10735–10739.PubMedCrossRefGoogle Scholar
  15. Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet. 1992;2:113–118.PubMedCrossRefGoogle Scholar
  16. Gu Y, Nakamura T, Alder H, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992;71:701–708.PubMedCrossRefGoogle Scholar
  17. Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71:691–700.PubMedCrossRefGoogle Scholar
  18. Ford AM, Ridge SA, Cabrera ME, et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature. 1993;363:358–360.PubMedCrossRefGoogle Scholar
  19. Megonigal MD, Rappaport EF, Jones DH, et al. t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Proc Natl Acad Sci U S A. 1998;95:6413–6418.PubMedCrossRefGoogle Scholar
  20. Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood. 2002;100:3710–3718.PubMedCrossRefGoogle Scholar
  21. Hess JL. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med. 2004;10:500–507.PubMedCrossRefGoogle Scholar
  22. Takeda S, Chen DY, Westergard TD, et al. Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression. Genes Dev. 2006;20:2397–2409.PubMedCrossRefGoogle Scholar
  23. Liu H, Cheng EH, Hsieh JJ. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. Genes Dev. 2007;21:2385–2398.PubMedCrossRefGoogle Scholar
  24. Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–47PubMedCrossRefGoogle Scholar
  25. Meyer C, Schneider B, Jakob S, et al. The MLL recombinome of acute leukemias. Leukemia. 2006;20:777–784.PubMedCrossRefGoogle Scholar
  26. Ayton PM, Cleary ML. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003;17:2298–2307.PubMedCrossRefGoogle Scholar
  27. Martin ME, Milne TA, Bloyer S, et al. Dimerization of MLL fusion proteins immortalizes hematopoietic cells. Cancer Cell. 2003;4:197–207.PubMedCrossRefGoogle Scholar
  28. Wong P, Iwasaki M, Somervaille TC, So CW, Cleary ML. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 2007.Google Scholar
  29. Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10:257–268.PubMedCrossRefGoogle Scholar
  30. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–822.PubMedCrossRefGoogle Scholar
  31. Wang J, Iwasaki H, Krivtsov A, et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 2005;24:368–381.PubMedCrossRefGoogle Scholar
  32. FDA. Challenges and opportunity on the critical path to new medical products. 2004.Google Scholar
  33. Brown P, Small D. FLT3 inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. European journal of cancer (Oxford, England : 1990). 2004;40:707.PubMedCrossRefGoogle Scholar
  34. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, UK. 2003;17:1738.CrossRefGoogle Scholar
  35. Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089.PubMedGoogle Scholar
  36. Rosnet O, Buhring HJ, Marchetto S, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–248.PubMedGoogle Scholar
  37. Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80:2584–2593.PubMedGoogle Scholar
  38. Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1:133–143.PubMedCrossRefGoogle Scholar
  39. Ross ME, Zhou X, Song G, et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood. 2003;102:2951–2959.PubMedCrossRefGoogle Scholar
  40. Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267.PubMedCrossRefGoogle Scholar
  41. Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia. 1996;10:588–599.PubMedGoogle Scholar
  42. Meierhoff G, Dehmel U, Gruss HJ, et al. Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines. Leukemia. 1995;9:1368–1372.PubMedGoogle Scholar
  43. Brasel K, Escobar S, Anderberg R, de Vries P, Gruss HJ, Lyman SD. Expression of the flt3 receptor and its ligand on hematopoietic cells. Leukemia. 1995;9:1212–1218.PubMedGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113:983–988.PubMedCrossRefGoogle Scholar
  46. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918.PubMedGoogle Scholar
  47. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia. 1998;12:301–310.PubMedCrossRefGoogle Scholar
  48. Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukoc Biol. 1999;65:372–380.PubMedGoogle Scholar
  49. Zhang S, Broxmeyer HE. Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase. Biochem Biophys Res Commun. 2000;277:195–199.PubMedCrossRefGoogle Scholar
  50. Zhang S, Fukuda S, Lee Y, et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J Exp Med. 2000;192:719–728.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. Kiyoi H, Ohno R, Ueda R, Saito H, Naoe T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene. 2002;21:2555–2563.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. Armstrong SA, Mabon ME, Silverman LB, et al. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood. 2004;103:3544–3546.PubMedCrossRefGoogle Scholar
  55. Taketani T, Taki T, Sugita K, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085–1088.PubMedCrossRefGoogle Scholar
  56. Kelly LM, Kutok JL, Williams IR, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A. 2002;99:8283–8288.PubMedCrossRefGoogle Scholar
  57. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood. 2002;99:310–318.PubMedCrossRefGoogle Scholar
  58. Li L, Piloto O, Nguyen HB, et al. Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model. Blood. 2008;111:3849–3858.PubMedCrossRefGoogle Scholar
  59. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. Brown P, Meshinchi S, Levis M, et al. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood. 2004;104:1841.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. Brown P, Levis M, Shurtleff S, Campana D, Downing J, Small D. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood. 2005;105:812–820.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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: official journal of the Leukemia Society of America, Leukemia Research Fund, UK. 2006;20:1368.Google Scholar
  68. Piloto O, Nguyen B, Huso D, et al. IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples. Cancer research. 2006;66:4843.PubMedCrossRefGoogle Scholar
  69. Piloto O, Levis M, Huso D, et al. Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. Cancer Res. 2005;65:1514–1522.PubMedCrossRefGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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. ASH Annual Meeting Abstracts. 2005;106:403.Google Scholar
  72. Robinson BW, Behling KC, Gupta M, et al. Abundant anti-apoptotic BCL-2 is a molecular target in leukaemias with t(4;11) translocation. Br J Haematol. 2008;141:827–839.PubMedCrossRefGoogle Scholar
  73. Zhang AY, Robinson BW, Kao K, et al. Cell death regulatory gene expression correlates with MLL rearrangement status and prognostic clinical covariates in acute leukemia in infants. ASH Annual Meeting Abstracts. 2008;112:2255.Google Scholar
  74. Green D. Apoptotic pathways: ten minutes to dead. Cell. 2005;121:671–674.PubMedCrossRefGoogle Scholar
  75. Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111–121.PubMedCrossRefGoogle Scholar
  76. Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell. 2003;3:17–22.PubMedCrossRefGoogle Scholar
  77. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–219.PubMedCrossRefGoogle Scholar
  78. Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104:19512–19517.PubMedCrossRefGoogle Scholar
  79. Gewirtz AM, Sokol DL, Ratajczak MZ. Nucleic acid therapeutics: state of the art and future prospects. Blood. 1998;92:712–736.PubMedGoogle Scholar
  80. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2:183–192.PubMedCrossRefGoogle Scholar
  81. Garber K. Targeting mitochondria emerges as therapeutic strategy. J Natl Cancer Inst. 2005;97:1800–1801.PubMedCrossRefGoogle Scholar
  82. Nicholson DW. From bench to clinic with apoptosis based therapeutic agents. Nature. 2000;407:810–816.PubMedCrossRefGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. O’Brien SM, Cunningham CC, Golenkov AK, Turkina AG, Novick SC, Rai KR. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:7697–7702.PubMedCrossRefGoogle Scholar
  85. Waters JS, Webb A, Cunningham D, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkins lymphoma. J Clin Oncol. 2000;18:1812–1823.PubMedGoogle Scholar
  86. Deng X, Gao F, May WS, Jr. Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS. Blood. 2003;102:3179–3185.PubMedCrossRefGoogle Scholar
  87. Huang S, Okumura K, Sinicrope FA. BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2009;15:150–159.PubMedCrossRefGoogle Scholar
  88. Williamson NR, Fineran PC, Gristwood T, Chawrai SR, Leeper FJ, Salmond GP. Anticancer and immunosuppressive properties of bacterial prodiginines. Future Microbiol. 2007;2:605–618.PubMedCrossRefGoogle Scholar
  89. Campas C, Cosialls AM, Barragan M, et al. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol. 2006;34:1663–1669.PubMedCrossRefGoogle Scholar
  90. Galan P, Roue G, Villamor N, Campo E, Colomer D. The Small Molecule Pan-Bcl-2 Inhibitor GX15–070 Induces Apoptosis In Vitro in Mantle Cell Lymphoma (MCL) Cells and Exhibits a Synergistic Effect in Combination with the Proteasome Inhibitor Bortezomib. ASH Annual Meeting Abstracts. 2005;106:1490.Google Scholar
  91. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109:4441–4449.PubMedCrossRefGoogle Scholar
  92. Li J, Viallet J, Haura EB. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol. 2007.Google Scholar
  93. Li J, Viallet J, Haura EB. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol. 2008;61:525–534.PubMedCrossRefGoogle Scholar
  94. Martinez-Paniagua MA, Vega MI, Huerta-Yepez S, et al. Direct and enhanced cytotoxicity of the Bcl-2 family inhibitor GX15-070 on rituximab-sensitive and rituximab-resistant B-NHL clones. ASH Annual Meeting Abstracts. 2007.Google Scholar
  95. Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood. 2007;109:5430–5438.PubMedCrossRefGoogle Scholar
  96. Witters LM, Witkoski A, Planas-Silva MD, Berger M, Viallet J, Lipton A. Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor. Oncol Rep. 2007;17:465–469.PubMedGoogle Scholar
  97. Konopleva M, Watt J, Contractor R, et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 2008;68:3413–3420.PubMedCrossRefGoogle Scholar
  98. Bebb G, Muzik H, Nguyen S, Morris D, Stewart DA. In Vitro and In Vivo Anti Lymphoma Effect of GX15-070 in Mantle Cell Lymphoma. Blood (ASH Annual Meeting Abstracts). 2006;108:4756.Google Scholar
  99. Yazbeck VY, Georgakis GV, Li Y, McConkey D, Andreeff M, Younes A. Inhibition of the Pan-Bcl-2 Family by the Small Molecule GX15-070 Induces Apoptosis in Mantle Cell Lymphoma (MCL) Cells and Enhances the Activity of Two Proteasome Inhibitors (NPI-0052 and Bortezomib), and Doxorubicin Chemotherapy. Blood (ASH Annual Meeting Abstracts). 2006;108:2532.Google Scholar
  100. Hernandez-Ilizaliturri FJ, Iqbal A, Alam N, et al. Targeting BH3-Domain Anti-Apoptotic Proteins with GX15-070 Decreases DNA Synthesis, Induces Cell Death and Sensitizes Rituximab-Sensitive and Resistant Non-Hodgkins Lymphoma Cell Lines to the Anti-Tumor Activity of Chemotherapy Agents. Blood (ASH Annual Meeting Abstracts). 2006;108:2523.Google Scholar
  101. Hernandez-Ilizaliturri FJ, Bhat S, Iqbal A, Olejniczak S, Knight J, Czuczman MS. Targeting BH3-Domain Anti-Apoptotic Proteins with GX15-070 Significantly Increases Rituximab-Mediated Antibody Dependent Cellular Cytotoxicity (ADCC) and Complement Mediated Cytotoxicity (CMC) Against B-Cell Lymphomas. Blood (ASH Annual Meeting Abstracts). 2006;108:2502.Google Scholar
  102. Borthakur G, O’Brien S, Ravandi-Kashani F, et al. A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL). ASH Annual Meeting Abstracts. 2006;108:2654.Google Scholar
  103. Goy A, Ford P, Feldman T, et al. A phase 1 trial of the pan Bcl-2 family inhibitor obatoclax mesylate (GX15-070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma. ASH Annual Meeting Abstracts. 2007.Google Scholar
  104. O’Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305.PubMedCrossRefGoogle Scholar
  105. Schimmer AD, Brandwein J, O’Brien SM, et al. A phase I trial of the small molecule pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by continuous Infusion for up to four days to patients with hematological malignancies. ASH Annual Meeting Abstracts. 2007.Google Scholar
  106. Verstovsek S, Raza A, Schimmer AD, Viallet J, Kantarjian H. A Phase II trial of the small molecule Pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by a 24-h continuous infusion every 2 weeks to patients with chronic idiopathic myelofibrosis (CIMF). ASH Annual Meeting Abstracts. 2007.Google Scholar
  107. Goy A, Ford P, Feldman T, et al. A Phase 1 Trial of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) in Combination with Bortezomib in Patients with Relapsed/Refractory Mantle Cell Lymphoma. ASH Annual Meeting Abstracts. 2007;110:2569.Google Scholar
  108. Schimmer AD, Brandwein J, O’Brien SM, et al. A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by Continuous Infusion for up to Four Days to Patients with Hematological Malignancies. ASH Annual Meeting Abstracts. 2007;110:892.Google Scholar
  109. Stubbs MC, Faber J, Kung AL, Cameron S, Armstrong SA. HOXA9 represses bim expression in MLL rearranged leukemia: implications for drug therapy. ASH Annual Meeting Abstracts. 2007.Google Scholar
  110. Thomas M, Gessner A, Vornlocher HP, Hadwiger P, Greil J, Heidenreich O. Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. Blood. 2005;106:3559–3566.PubMedCrossRefGoogle Scholar
  111. Goldsmith KC, Liu X, Dam V, et al. BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma. Oncogene. 2006;25:4525–4533.PubMedCrossRefGoogle Scholar
  112. Xia SJ, Pressey JG, Barr FG. Molecular pathogenesis of rhabdomyosarcoma. Cancer Biol Ther. 2002;1:97–104.PubMedGoogle Scholar
  113. Bhojwani D, Kang H, Menezes RX, et al. Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children’s Oncology Group Study [corrected]. J Clin Oncol. 2008;26:4376–4384.PubMedCrossRefGoogle Scholar
  114. Flotho C, Coustan-Smith E, Pei D, et al. A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia. Blood. 2007;110:1271–1277.PubMedCrossRefGoogle Scholar
  115. Holleman A, den Boer ML, de Menezes RX, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood. 2006;107:769–776.PubMedCrossRefGoogle Scholar
  116. Bonapace L, Bornhauser BC, Cario G, et al. The BH3-Mimetic Obatoclax Restores the Response to Dexamethasone in Glucocorticoid-Resistant ALL through Induction of Autophagy. ASH Annual Meeting Abstracts. 2007;110:806.Google Scholar
  117. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–399.PubMedCrossRefGoogle Scholar
  118. Zhang AY, Robinson BW, Wang L-S, et al. Pan-Anti-Apoptotic BCL-2 Family Inhibitor, Obatoclax, Activates Autophagic Cell Death Pathway and Has Potent Cytotoxicity in Infant and Pediatric MLL-Rearranged Leukemias. ASH Annual Meeting Abstracts. 2008;112:2647.Google Scholar
  119. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4:151–175.PubMedGoogle Scholar
  120. Maiuri MC, Le Toumelin G, Criollo A, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. Embo J. 2007;26:2527–2539.PubMedCrossRefGoogle Scholar
  121. Zhang AY, Barrett JS, Danet-Desnoyers G, et al. Obatoclax Biodistribution in MLL leukemia NOG Mouse Model is predicted by modeling and simulation and shows high tissue penetration at clinically important sites. J Clin Pharmacol. 2008;48:1130.Google Scholar
  122. Zhang AY, Barrett JS, Beauparlant P, et al. Modeling and Simulation Approach to Advance Molecularly-Targeted Pro-Apoptotic Agents for Infant Leukemias. J Clin Pharmacol. 2007;47:1209.Google Scholar
  123. Kang MH, Kang YH, Szymanska B, et al. Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood. 2007.Google Scholar
  124. Trudel S, Stewart AK, Li Z, et al. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007;13:621–629.PubMedCrossRefGoogle Scholar
  125. Chauhan D, Velankar M, Brahmandam M, et al. A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 2007;26:2374–2380.PubMedCrossRefGoogle Scholar
  126. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375–388.PubMedCrossRefGoogle Scholar
  127. Kline MP, Rajkumar SV, Timm MM, et al. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia. 2007;21:1549–1560.PubMedCrossRefGoogle Scholar
  128. Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle. 2006;5:2778–2786.PubMedCrossRefGoogle Scholar
  129. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681.PubMedCrossRefGoogle Scholar
  130. Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173–183.PubMedCrossRefGoogle Scholar
  131. 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.PubMedCrossRefGoogle Scholar
  132. Brown P, Small D. FLT3 inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. Eur J Cancer. 2004;40:707–721, discussion 722–704.PubMedCrossRefGoogle Scholar
  133. Stam RW, den Boer ML, Schneider P, et al. Targeting FLT3 in primary MLL gene rearranged infant acute lymphoblastic leukemia. Blood. 2005.Google Scholar
  134. Stubbs MC, Armstrong SA. FLT3 as a therapeutic target in childhood acute leukemia. Curr Drug Targets. 2007;8:703–714.PubMedCrossRefGoogle Scholar
  135. Rodila RC, Kim JC, Ji QC, El-Shourbagy TA. A high-throughput, fully automated liquid/liquid extraction liquid chromatography/mass spectrometry method for the quantitation of a new investigational drug ABT-869 and its metabolite A-849529 in human plasma samples. Rapid Commun Mass Spectrom. 2006;20:3067–3075.PubMedCrossRefGoogle Scholar
  136. Carlson DM, Steinberg JL, Gordon G. Targeting the unmet medical need: the Abbott Laboratories oncology approach. Clin Adv Hematol Oncol. 2005;3:703–710.PubMedGoogle Scholar
  137. Dai Y, Hartandi K, Ji Z, et al. Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem. 2007;50:1584–1597.PubMedCrossRefGoogle Scholar
  138. Shankar DB, Li J, Tapang P, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood. 2007;109:3400–3408.PubMedCrossRefGoogle Scholar
  139. Albert DH, Tapang P, Magoc TJ, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006;5:995–1006.PubMedCrossRefGoogle Scholar
  140. 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.PubMedCrossRefGoogle Scholar
  141. Kohl TM, Hellinger C, Ahmed F, et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia. 2007.Google Scholar
  142. Kawagoe H, Kawagoe R, Sano K. Targeted down-regulation of MLL-AF9 with antisense oligodeoxyribonucleotide reduces the expression of the HOXA7 and -A10 genes and induces apoptosis in a human leukemia cell line, THP-1. Leukemia. 2001;15:1743–1749.PubMedCrossRefGoogle Scholar
  143. Niitsu N, Hayashi Y, Honma Y. Downregulation of MLL-CBP fusion gene expression is associated with differentiation of SN-1 cells with t(11;16)(q23;p13). Oncogene. 2001;20:375–384.PubMedCrossRefGoogle Scholar
  144. Akao Y, Mizoguchi H, Misiura K, et al. Antisense oligodeoxyribonucleotide against the MLL-LTG19 chimeric transcript inhibits cell growth and induces apoptosis in cells of an infantile leukemia cell line carrying the t(11;19) chromosomal translocation. Cancer Res. 1998;58:3773–3776.PubMedGoogle Scholar
  145. Bitoun E, Oliver PL, Davies KE. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum Mol Genet. 2007;16:92–106.PubMedCrossRefGoogle Scholar
  146. Srinivasan RS, Nesbit JB, Marrero L, Erfurth F, LaRussa VF, Hemenway CS. The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells. Leukemia. 2004;18:1364–1372.PubMedCrossRefGoogle Scholar
  147. Erfurth F, Hemenway CS, de Erkenez AC, Domer PH. MLL fusion partners AF4 and AF9 interact at subnuclear foci. Leukemia. 2004;18:92–102.PubMedCrossRefGoogle Scholar
  148. Palermo CM, Bennett CA, Winters AC, Hemenway CS. The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells. Leuk Res. 2008;32:633–642.PubMedCrossRefGoogle Scholar
  149. Bennett CA, Winters AC, Barretto NN, Hemenway CS. Molecular targeting of MLL-rearranged leukemia cell lines with the synthetic peptide PFWT synergistically enhances the cytotoxic effect of established chemotherapeutic agents. Leuk Res. 2009;33:937–947.PubMedCrossRefGoogle Scholar
  150. Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 2008;455:1205–1209.PubMedCrossRefGoogle Scholar
  151. Wiech H, Buchner J, Zimmermann R, Jakob U. Hsp90 chaperones protein folding in vitro. Nature. 1992;358:169–170.PubMedCrossRefGoogle Scholar
  152. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell. 1997;89:239–250.PubMedCrossRefGoogle Scholar
  153. Terasawa K, Minami M, Minami Y. Constantly updated knowledge of Hsp90. J Biochem. 2005;137:443–447.PubMedCrossRefGoogle Scholar
  154. Imai J, Maruya M, Yashiroda H, Yahara I, Tanaka K. The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome. EMBO J. 2003;22:3557–3567.PubMedCrossRefGoogle Scholar
  155. Yao Q, Nishiuchi R, Li Q, Kumar AR, Hudson WA, Kersey JH. FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Clin Cancer Res. 2003;9:4483–4493.PubMedGoogle Scholar
  156. Belova L, Brickley DR, Ky B, Sharma SK, Conzen SD. Hsp90 regulates the phosphorylation and activity of serum- and glucocorticoid-regulated kinase-1. J Biol Chem. 2008;283:18821–18831.PubMedCrossRefGoogle Scholar
  157. Fujita N, Sato S, Ishida A, Tsuruo T. Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2002;277:10346–10353.PubMedCrossRefGoogle Scholar
  158. Zhang R, Luo D, Miao R, et al. Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene. 2005;24:3954–3963.PubMedCrossRefGoogle Scholar
  159. Picard D. Hsp90 invades the outside. Nat Cell Biol. 2004;6:479–480.PubMedCrossRefGoogle Scholar
  160. Eustace BK, Jay DG. Extracellular roles for the molecular chaperone, hsp90. Cell Cycle. 2004;3:1098–1100.PubMedCrossRefGoogle Scholar
  161. Eustace BK, Sakurai T, Stewart JK, et al. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol. 2004;6:507–514.PubMedCrossRefGoogle Scholar
  162. Yocum AK, Busch CM, Felix CA, Blair IA. Proteomics-based strategy to identify biomarkers and pharmacological targets in leukemias with t(4;11) translocations. J Proteome Res. 2006;5:2743–2753.PubMedCrossRefGoogle Scholar
  163. Yao Q, Weigel B, Kersey J. Synergism between etoposide and 17-AAG in leukemia cells: critical roles for Hsp90, FLT3, topoisomerase II, Chk1, and Rad51. Clin Cancer Res. 2007;13:1591–1600.PubMedCrossRefGoogle Scholar
  164. Yao Q, Nishiuchi R, Kitamura T, Kersey JH. Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway. Leukemia. 2005;19:1605–1612.PubMedCrossRefGoogle Scholar
  165. Tonelli R, Sartini R, Fronza R, et al. G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent. Leukemia. 2006;20:1307–1310.PubMedCrossRefGoogle Scholar
  166. Niitsu N, Hayashi Y, Sugita K, Honma Y. Sensitization by 5-aza-2′-deoxycytidine of leukaemia cells with MLL abnormalities to induction of differentiation by all-trans retinoic acid and 1alpha,25-dihydroxyvitamin D3. Br J Haematol. 2001;112:315–326.PubMedCrossRefGoogle Scholar
  167. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281.PubMedCrossRefGoogle Scholar
  168. Brown VI, Fang J, Alcorn K, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003;100:15113–15118.PubMedCrossRefGoogle Scholar
  169. Teachey DT, Sheen C, Hall J, et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood. 2008;112:2020–2023.PubMedCrossRefGoogle Scholar
  170. Wei G, Twomey D, Lamb J, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell. 2006;10:331–342.PubMedCrossRefGoogle Scholar
  171. Pieters R, den Boer ML, Durian M, et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants. Leukemia. 1998;12:1344–1348.PubMedCrossRefGoogle Scholar
  172. Palle J, Frost BM, Forestier E, et al. Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage. Br J Haematol. 2005;129:189–198.PubMedCrossRefGoogle Scholar
  173. Zwaan CM, Reinhardt D, Corbacioglu S, et al. Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood. 2003;101:3868–3871.PubMedCrossRefGoogle Scholar
  174. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Oncology, Department of Pediatrics, The Children’s Hospital of PhiladelphiaUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations