The Emerging Era of Targeted Therapy in Childhood Acute Lymphoblastic Leukemia



One of the most fundamental goals of modern cancer research is to develop more effective therapies that specifically target the cancer cell while sparing normal cells from the collateral damage that is common to conventional therapies. The cornerstone of current cancer treatment depends on drugs associated with a very narrow therapeutic index in that the effective dose and the toxic dose frequently overlap. While progress in pediatric oncology, specifically, improved cure rates for the most common childhood malignancy, acute lymphoblastic leukemia (ALL), has outpaced improvements in other cancer subtypes, treatment for ALL still relies on conventional cytotoxic agents thereby exposing children to considerable short- and long-term side effects.


Acute Lymphoblastic Leukemia Cancer Stem Cell Gemtuzumab Ozogamicin Event Free Survival Conventional Cytotoxic Agent 
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.



This work was supported by the Penelope London Foundation, the Friedman Fund for Childhood Leukemia, and the Walter Family Pediatric Leukemia Fund. The authors thank Drs. Teena Bhatla and Elizabeth Raetz for review of the manuscript.


  1. Agnes, F., B. Shamoon, et al. (1994). “Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III.” Gene 145(2): 283–8.PubMedCrossRefGoogle Scholar
  2. Al-Hajj, M., M. S. Wicha, et al. (2003). “Prospective identification of tumorigenic breast cancer cells.” Proc Natl Acad Sci USA 100(7): 3983–8.PubMedCrossRefGoogle Scholar
  3. Arico, M., M. G. Valsecchi, et al. (2000). “Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.” N Engl J Med 342(14): 998–1006.PubMedCrossRefGoogle Scholar
  4. Armstrong, S. A., A. L. Kung, et al. (2003). “Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.” Cancer Cell 3(2): 173–83.PubMedCrossRefGoogle Scholar
  5. Armstrong, S. A., M. E. Mabon, et al. (2004). “FLT3 mutations in childhood acute lymphoblastic leukemia.” Blood 103(9): 3544–6.PubMedCrossRefGoogle Scholar
  6. Armstrong, S. A., J. E. Staunton, et al. (2002). “MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.” Nat Genet 30(1): 41–7.PubMedCrossRefGoogle Scholar
  7. Balduzzi, A., V. Rossi, et al. (2003). “Molecular remission induced by gemtuzumab ozogamicin associated with donor lymphocyte infusions in t(4;11) acute lymphoblastic leukemia relapsed after transplantation.” Leukemia 17(11): 2247–8.PubMedCrossRefGoogle Scholar
  8. Bargou, R., E. Leo, et al. (2008). “Tumor regression in cancer patients by very low doses of a T cell-engaging antibody.” Science 321(5891): 974–7.PubMedCrossRefGoogle Scholar
  9. Bonnet, D. and J. E. Dick (1997). “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.” Nat Med 3(7): 730–7.PubMedCrossRefGoogle Scholar
  10. Branford, S., Z. Rudzki, et al. (2003). “Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.” Blood 102(1): 276–83.PubMedCrossRefGoogle Scholar
  11. Brasel, K., S. Escobar, et al. (1995). “Expression of the flt3 receptor and its ligand on hematopoietic cells.” Leukemia 9(7): 1212­–8.PubMedGoogle Scholar
  12. Brown, P., M. Levis, et al. (2006). “Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner.” Leukemia 20(8): 1368–76.PubMedCrossRefGoogle Scholar
  13. Brown, P., M. Levis, et al. (2005). “FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression.” Blood 105(2): 812–20.PubMedCrossRefGoogle Scholar
  14. Carnahan, J., P. Wang, et al. (2003). “Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties.” Clin Cancer Res 9(10 Pt 2): 3982S–90S.PubMedGoogle Scholar
  15. Carow, C. E., M. Levenstein, et al. (1996). “Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias.” Blood 87(3): 1089–96.PubMedGoogle Scholar
  16. Castor, A., L. Nilsson, et al. (2005). “Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.” Nat Med 11(6): 630–7.PubMedCrossRefGoogle Scholar
  17. Chan, L. C., K. K. Karhi, et al. (1987). “A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia.” Nature 325(6105): 635–7.PubMedCrossRefGoogle Scholar
  18. Chan, S. M., A. P. Weng, et al. (2007). “Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.” Blood 110(1): 278–86.PubMedCrossRefGoogle Scholar
  19. Clark, S. S., J. McLaughlin, et al. (1988). “Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL).” Science 239(4841 Pt 1): 775–7.PubMedCrossRefGoogle Scholar
  20. Claviez, A., C. Eckert, et al. (2006). “Rituximab plus chemotherapy in children with relapsed or refractory CD20-positive B-cell precursor acute lymphoblastic leukemia.” Haematologica 91(2): 272–3.PubMedGoogle Scholar
  21. Cobaleda, C., N. Gutierrez-Cianca, et al. (2000). “A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia.” Blood 95(3): 1007–13.PubMedGoogle Scholar
  22. Cotter, M., S. Rooney, et al. (2003). “Successful use of gemtuzumab ozogamicin in a child with relapsed CD33-positive acute lymphoblastic leukaemia.” Br J Haematol 122(4): 687–8.PubMedCrossRefGoogle Scholar
  23. Cox, C. V., P. Diamanti, et al. (2009). “Expression of CD133 on leukemia initiating cells in childhood ALL.” Blood 113(14): 3287–96.PubMedCrossRefGoogle Scholar
  24. Cox, C. V., R. S. Evely, et al. (2004). “Characterization of acute lymphoblastic leukemia progenitor cells.” Blood 104(9): 2919–25.PubMedCrossRefGoogle Scholar
  25. Demarest, R. M., F. Ratti, et al. (2008). “It’s T-ALL about Notch.” Oncogene 27(38): 5082–91.PubMedCrossRefGoogle Scholar
  26. Drexler, H. G. (1996). “Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells.” Leukemia 10(4): 588–99.PubMedGoogle Scholar
  27. Druker, B. J., F. Guilhot, et al. (2006). “Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.” N Engl J Med 355(23): 2408–17.PubMedCrossRefGoogle Scholar
  28. Druker, B. J., C. L. Sawyers, et al. (2001). “Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.” N Engl J Med 344(14): 1038–42.PubMedCrossRefGoogle Scholar
  29. Druker, B. J., S. Tamura, et al. (1996). “Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.” Nat Med 2(5): 561–6.PubMedCrossRefGoogle Scholar
  30. Dworzak, M. N., A. Schumich, et al. (2008). “CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy.” Blood 112(10): 3982–8.PubMedCrossRefGoogle Scholar
  31. Ellisen, L. W., J. Bird, et al. (1991). “TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.” Cell 66(4): 649–61.PubMedCrossRefGoogle Scholar
  32. Feugier, P., A. Van Hoof, et al. (2005). “Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte.” J Clin Oncol 23(18): 4117–26.PubMedCrossRefGoogle Scholar
  33. Fortini, M. E. and S. Artavanis-Tsakonas (1994). “The suppressor of hairless protein participates in notch receptor signaling.” Cell 79(2): 273–82.PubMedCrossRefGoogle Scholar
  34. Frampton, J. E. and A. J. Wagstaff (2003). “Alemtuzumab.” Drugs 63(12): 1229–43; discussion 1245–6.PubMedCrossRefGoogle Scholar
  35. Frohling, S., C. Scholl, et al. (2007). “Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.” Cancer Cell 12(6): 501–13.PubMedCrossRefGoogle Scholar
  36. Fryer, C. J., J. B. White, et al. (2004). “Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.” Mol Cell 16(4): 509–20.PubMedCrossRefGoogle Scholar
  37. Golay, J., N. Di Gaetano, et al. (2005). “Gemtuzumab ozogamicin (Mylotarg) has therapeutic activity against CD33 acute lymphoblastic leukaemias in vitro and in vivo.” Br J Haematol 128(3): 310–7.PubMedCrossRefGoogle Scholar
  38. Gordon, W. R., D. Vardar-Ulu, et al. (2007). “Structural basis for autoinhibition of Notch.” Nat Struct Mol Biol 14(4): 295–300.PubMedCrossRefGoogle Scholar
  39. Griffin, T. C., S. Weitzman, et al. (2009). “A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group.” Pediatr Blood Cancer 52(2): 177–81.PubMedCrossRefGoogle Scholar
  40. Grossbard, M. L., J. M. Lambert, et al. (1993). “Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.” J Clin Oncol 11(4): 726–37.PubMedGoogle Scholar
  41. Harris, M. (2004). “Monoclonal antibodies as therapeutic agents for cancer.” Lancet Oncol 5(5): 292–302.PubMedCrossRefGoogle Scholar
  42. Hekman, A., A. Honselaar, et al. (1991). “Initial experience with treatment of human B cell lymphoma with anti-CD19 monoclonal antibody.” Cancer Immunol Immunother 32(6): 364–72.PubMedCrossRefGoogle Scholar
  43. Hilden, J. M., P. A. Dinndorf, et al. (2006). “Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group.” Blood 108(2): 441–51.PubMedCrossRefGoogle Scholar
  44. Hong, D., R. Gupta, et al. (2008). “Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia.” Science 319(5861): 336–9.PubMedCrossRefGoogle Scholar
  45. Horton, H. M., M. J. Bernett, et al. (2008). “Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia.” Cancer Res 68(19): 8049–57.PubMedCrossRefGoogle Scholar
  46. Jeha, S., F. Behm, et al. (2006). “Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia.” Blood 108(10): 3302–4.PubMedCrossRefGoogle Scholar
  47. Leonard, J. P., M. Coleman, et al. (2005). “Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkins lymphoma.” J Clin Oncol 23(22): 5044–51.PubMedCrossRefGoogle Scholar
  48. Lleo, A. (2008). “Activity of gamma-secretase on substrates other than APP.” Curr Top Med Chem 8(1): 9–16.PubMedCrossRefGoogle Scholar
  49. Malecki, M. J., C. Sanchez-Irizarry, et al. (2006). “Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.” Mol Cell Biol 26(12): 4642–51.PubMedCrossRefGoogle Scholar
  50. Meshinchi, S., W. G. Woods, et al. (2001). “Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia.” Blood 97(1): 89–94.PubMedCrossRefGoogle Scholar
  51. Molhoj, M., S. Crommer, et al. (2007). “CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis.” Mol Immunol 44(8): 1935–43.PubMedCrossRefGoogle Scholar
  52. Moorman, A. V., C. J. Harrison, et al. (2007). “Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.” Blood 109(8): 3189–97.PubMedCrossRefGoogle Scholar
  53. Morris, E. S. and A. Vora (2007). “Remission induction with single agent Rituximab in a child with multiply relapsed precursor-B ALL.” Br J Haematol 139(2): 344–5.PubMedCrossRefGoogle Scholar
  54. Nakao, M., S. Yokota, et al. (1996). “Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.” Leukemia 10(12): 1911–8.PubMedGoogle Scholar
  55. Nefedova, Y. and D. Gabrilovich (2008). “Mechanisms and clinical prospects of Notch inhibitors in the therapy of hematological malignancies.” Drug Resist Updat 11(6): 210–8.PubMedCrossRefGoogle Scholar
  56. O’Brien, C. A., A. Pollett, et al. (2007). “A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.” Nature 445(7123): 106–10.PubMedCrossRefGoogle Scholar
  57. O’Hare, T., C. A. Eide, et al. (2007). “Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.” Blood 110(7): 2242–9.PubMedCrossRefGoogle Scholar
  58. Oberg, C., J. Li, et al. (2001). “The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.” J Biol Chem 276(38): 35847–53.PubMedCrossRefGoogle Scholar
  59. Ottmann, O. G., B. J. Druker, et al. (2002). “A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.” Blood 100(6): 1965–71.PubMedCrossRefGoogle Scholar
  60. Palomero, T. and A. Ferrando (2008). “Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-cell acute lymphoblastic leukemias and lymphomas.” Clin Cancer Res 14(17): 5314–7.PubMedCrossRefGoogle Scholar
  61. Palomero, T., W. K. Lim, et al. (2006). “NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.” Proc Natl Acad Sci USA 103(48): 18261–6.PubMedCrossRefGoogle Scholar
  62. Palomero, T., M. L. Sulis, et al. (2007). “Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.” Nat Med 13(10): 1203–10.PubMedCrossRefGoogle Scholar
  63. Pear, W. S., J. C. Aster, et al. (1996). “Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.” J Exp Med 183(5): 2283–91.PubMedCrossRefGoogle Scholar
  64. Pfreundschuh, M., L. Trumper, et al. (2006). “CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.” Lancet Oncol 7(5): 379–91.PubMedCrossRefGoogle Scholar
  65. Pieters, R., M. Schrappe, et al. (2007). “A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.” Lancet 370(9583): 240–50.PubMedCrossRefGoogle Scholar
  66. Pui, C. H., P. S. Gaynon, et al. (2002). “Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.” Lancet 359(9321): 1909–15.PubMedCrossRefGoogle Scholar
  67. Putti, M. C., R. Rondelli, et al. (1998). “Expression of myeloid markers lacks prognostic impact in children treated for acute lymphoblastic leukemia: Italian experience in AIEOP-ALL 88-91 studies.” Blood 92(3): 795–801.PubMedGoogle Scholar
  68. Raetz, E. A., M. S. Cairo, et al. (2008). “Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study.” J Clin Oncol 26(22): 3756–62.PubMedCrossRefGoogle Scholar
  69. Real, P. J., V. Tosello, et al. (2009). “Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.” Nat Med 15(1): 50–8.PubMedCrossRefGoogle Scholar
  70. Ribeiro, R. C., A. Broniscer, et al. (1997). “Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts.” Leukemia 11(9): 1493–6.PubMedCrossRefGoogle Scholar
  71. Rosnet, O., H. J. Buhring, et al. (1996). “Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells.” Leukemia 10(2): 238–48.PubMedGoogle Scholar
  72. Rowland, A. J., G. A. Pietersz, et al. (1993). “Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates.” Cancer Immunol Immunother 37(3): 195–202.PubMedCrossRefGoogle Scholar
  73. Schnittger, S., C. Schoch, et al. (2002). “Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.” Blood 100(1): 59–66.PubMedCrossRefGoogle Scholar
  74. Schrappe, M., M. Arico, et al. (1998). “Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.” Blood 92(8): 2730–41.PubMedGoogle Scholar
  75. Schroeter, E. H., J. A. Kisslinger, et al. (1998). “Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.” Nature 393(6683): 382–6.PubMedCrossRefGoogle Scholar
  76. Schultz, K. R., D. J. Pullen, et al. (2007). “Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG).” Blood 109(3): 926–35.PubMedCrossRefGoogle Scholar
  77. Secker-Walker, L. M., H. G. Prentice, et al. (1997). “Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia Working Party.” Br J Haematol 96(3): 601–10.PubMedCrossRefGoogle Scholar
  78. Shah, N. P., C. Tran, et al. (2004). “Overriding imatinib resistance with a novel ABL kinase inhibitor.” Science 305(5682): 399–401.PubMedCrossRefGoogle Scholar
  79. Sievers, E. L., R. A. Larson, et al. (2001). “Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.” J Clin Oncol 19(13): 3244–54.PubMedGoogle Scholar
  80. Silverman, L. B. (2007). “Acute lymphoblastic leukemia in infancy.” Pediatr Blood Cancer 49(7 Suppl): 1070–3.PubMedCrossRefGoogle Scholar
  81. Smith, B. D., M. Levis, et al. (2004). “Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia.” Blood 103(10): 3669–76.PubMedCrossRefGoogle Scholar
  82. Stam, R. W., M. L. den Boer, et al. (2007a). “D-HPLC analysis of the entire FLT3 gene in MLL rearranged and hyperdiploid acute lymphoblastic leukemia.” Haematologica 92(11): 1565–8.PubMedCrossRefGoogle Scholar
  83. Stam, R. W., M. L. den Boer, et al. (2005). “Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia.” Blood 106(7): 2484–90.PubMedCrossRefGoogle Scholar
  84. Stam, R. W., P. Schneider, et al. (2007b). “Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia.” Blood 110(7): 2774–5.PubMedCrossRefGoogle Scholar
  85. Stirewalt, D. L. and J. P. Radich (2003). “The role of FLT3 in haematopoietic malignancies.” Nat Rev Cancer 3(9): 650–65.PubMedCrossRefGoogle Scholar
  86. Stone, R. M., D. J. DeAngelo, et al. (2005). “Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412.” Blood 105(1): 54–60.PubMedCrossRefGoogle Scholar
  87. Taketani, T., T. Taki, et al. (2004). “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 103(3): 1085–8.PubMedCrossRefGoogle Scholar
  88. Talpaz, M., N. P. Shah, et al. (2006). “Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.” N Engl J Med 354(24): 2531–41.PubMedCrossRefGoogle Scholar
  89. Thiede, C., C. Steudel, et al. (2002). “Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.” Blood 99(12): 4326–35.PubMedCrossRefGoogle Scholar
  90. Thomas, D. A., S. Faderl, et al. (2004). “Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate.” Blood 103(12): 4396–407.PubMedCrossRefGoogle Scholar
  91. Thomas, D. A., S. Faderl, et al. (2006). “Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.” Cancer 106(7): 1569–80.PubMedCrossRefGoogle Scholar
  92. Thomas, D. A., S. O’Brien, et al. (2008). “Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia.” Blood 113: 6330–37.PubMedCrossRefGoogle Scholar
  93. Thompson, B. J., S. Buonamici, et al. (2007). “The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.” J Exp Med 204(8): 1825–35.PubMedCrossRefGoogle Scholar
  94. Tibes, R., M. J. Keating, et al. (2006). “Activity of alemtuzumab in patients with CD52-positive acute leukemia.” Cancer 106(12): 2645–51.PubMedCrossRefGoogle Scholar
  95. Wang, J. C., T. Lapidot, et al. (1998). “High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase.” Blood 91(7): 2406–14.PubMedGoogle Scholar
  96. Weisberg, E., C. Boulton, et al. (2002). “Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.” Cancer Cell 1(5): 433–43.PubMedCrossRefGoogle Scholar
  97. Weisberg, E., P. W. Manley, et al. (2005). “Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.” Cancer Cell 7(2): 129–41.PubMedCrossRefGoogle Scholar
  98. Weng, A. P., A. A. Ferrando, et al. (2004). “Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.” Science 306(5694): 269–71.PubMedCrossRefGoogle Scholar
  99. Xia, M. Q., G. Hale, et al. (1993). “Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis.” Biochem J 293(Pt 3): 633–40.PubMedGoogle Scholar
  100. Yeoh, E. J., M. E. Ross, et al. (2002). “Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.” Cancer Cell 1(2): 133–43.PubMedCrossRefGoogle Scholar
  101. Zwaan, C. M., V. H. J. van der Velden et al. (2008). “Dasatinib in children and adolescents with relapsed or refractory leukemia: interim results of the CA180-018 phase I study from the ITCC consortium.” Blood 112: 3241.Google Scholar
  102. Zwaan, C. M., D. Reinhardt, et al. (2003). “Gemtuzumab ozogamicin in pediatric CD33-positive acute lymphoblastic leukemia: first clinical experiences and relation with cellular sensitivity to single agent calicheamicin.” Leukemia 17(2): 468–70.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.New York University Cancer InstituteNew YorkUSA

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