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Molecularly Targeted Therapies in Pediatric Myelodysplastic Syndromes

  • Lia Gore
Chapter

Abstract

New technologies have improved our understanding of hematopoietic and leukemia biology, and expanding knowledge of underlying molecular pathways and genomic aberrations is facilitating the development of new therapies for relapsed and refractory disease (Bhojwani et al. 2006; Carroll et al. 2006). Myelodysplasia and associated syndromes constitute a broad range of bone marrow dysfunction, characterized by variable clinical features; cytopenias due to bone marrow production and/or dysfunction and insufficiencies are typical. Clinical symptoms are frequently due to anemia, neutropenia, and/or thrombocytopenia, and transfusion dependence is common although not universal. The progression from myelodysplastic syndromes (MDS) to leukemia, particularly in children, is unequivocal, although the time course over which this occurs is highly variable. Risk factors for progression and lability of disease have been identified, and great effort is being made to identify the molecular triggers in MDS that are both causative and clinically relevant.

Keywords

Valproic Acid Acute Promyelocytic Leukemia HDAC Inhibitor Acute Myelogenous Leukemia Arsenic Trioxide 
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.

References

  1. Bhojwani D, Kang H, Moskowitz NP, et al. Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood 2006:108(2):711–717.PubMedCrossRefGoogle Scholar
  2. Carroll WL, Bhojwani D, Min DJ, et al. Childhood acute lymphoblastic leukemia in the age of genomics. Pediatr Blood Cancer 2006:46(5):570–578.PubMedCrossRefGoogle Scholar
  3. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008:112(1):45–52.PubMedCrossRefGoogle Scholar
  4. Finn R. Medicare analysis suggests MDS is “severely underestimated.” Oncol Rep 2009(Spring): 21(1):37–38.Google Scholar
  5. Ma X, Does M, Raza A, et al. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 2007:109(8):1536–1542.PubMedCrossRefGoogle Scholar
  6. Locatelli F, Zecca M, Pession A, et al. Myelodysplastic syndromes: the pediatric point of view. Haematologica 1995:80(3):268–279.PubMedGoogle Scholar
  7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009:113(13):2895–2901.PubMedCrossRefGoogle Scholar
  8. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982:51(2):189–199.PubMedGoogle Scholar
  9. Jaffe ES, Harris NL, Stein H, et al. Tumours of the haematolpoietic and lyphoid tissues. In: Tumours WHOCo, editor. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2001Google Scholar
  10. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997:89(6):2079–2088.PubMedGoogle Scholar
  11. Kaushansky. Erratum. Blood 1998:91(3):1100.Google Scholar
  12. Hasle H, Niemeyer CM, Chessells JM, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 2003:17(2):277–282.PubMedCrossRefGoogle Scholar
  13. Mandel K, Dror Y, Poon A, et al. A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 2002:24(7):596–605.PubMedCrossRefGoogle Scholar
  14. Lorand-Metze I, Pinheiro MP, Ribeiro E, et al. Factors influencing survival in myelodysplastic syndromes in a Brazilian population: comparison of FAB and WHO classifications. Leuk Res 2004:28(6):587–594.PubMedCrossRefGoogle Scholar
  15. Occhipinti E, Correa H, Yu L, et al. Comparison of two new classifications for pediatric myelodysplastic and myeloproliferative disorders. Pediatr Blood Cancer 2005:44(3):240–244.PubMedCrossRefGoogle Scholar
  16. Alter BP. Fanconi’s anemia and malignancies. Am J Hematol 1996:53(2):99–110.PubMedCrossRefGoogle Scholar
  17. Alter BP. Bone marrow failure syndromes in children. Pediatr Clin North Am 2002:49(5): 973–988.PubMedCrossRefGoogle Scholar
  18. Homans AC, Verissimo AM, Vlacha V. Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 1993:15(4):392–399.PubMedGoogle Scholar
  19. Creutzig U, Ritter J, Vormoor J, et al. Myelodysplasia and acute myelogenous leukemia in Down’s syndrome. A report of 40 children of the AML-BFM Study Group. Leukemia 1996:10(11): 1677–1686.Google Scholar
  20. Rischewski JR, Clausen H, Leber V, et al. A heterozygous frameshift mutation in the Fanconi anemia C gene in familial T-ALL and secondary malignancy. Klin Padiatr 2000:212(4):174–176.PubMedCrossRefGoogle Scholar
  21. Surico G, Muggeo P, Rigillo N, et al. Concurrent Langerhans cell histiocytosis and myelodysplasia in children. Med Pediatr Oncol 2000:35(4):421–425.PubMedCrossRefGoogle Scholar
  22. Cetin M, Hicsonmez G, Gogus S. Myelodysplastic syndrome associated with Griscelli syndrome. Leuk Res 1998:22(9):859–862.PubMedCrossRefGoogle Scholar
  23. Ohara A, Kojima S, Hamajima N, et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997:90(3):1009–1013.PubMedGoogle Scholar
  24. Winick NJ, McKenna RW, Shuster JJ, et al. Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol 1993:11:209–217.PubMedGoogle Scholar
  25. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 1991:325(24):1682–1687.PubMedCrossRefGoogle Scholar
  26. Tew KD, Colvin OM, Chabner BA. Alkylating agents. In: Chabner BA, Longo DL, editors. Cancer Chemotherapy and Biotherapy. Third ed. Phliadelphia: Lippincott Williams & Wilkins; 2001, pp 397–398.Google Scholar
  27. Smith MA, McCaffrey RP, Karp JE. The secondary leukemias: challenges and research directions. J Natl Cancer Inst 1996:88:407–418.PubMedCrossRefGoogle Scholar
  28. Bo J, Schroder H, Kristinsson J, et al. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer 1999:86(6):1080–1086.PubMedCrossRefGoogle Scholar
  29. Felix CA, Hosler MR, Winick NJ, et al. ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood 1995:85(11):3250–3256.PubMedGoogle Scholar
  30. Privitera E, Wang W, Raimondi SC. Monosomy 7 and unbalanced t(1;7) in an adolescent boy with myelodysplastic syndrome. Leukemia 1992:6(7):742–745.PubMedGoogle Scholar
  31. Yesilipek MA, Luleci G, Velipasaoglu S, et al. Monosomy 7 myelodysplasia in childhood. Two case reports. Acta Haematol 1994:92(1):36–38.PubMedCrossRefGoogle Scholar
  32. Maris JM, Wiersma SR, Mahgoub N, et al. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 1997:79(7): 1438–1446.PubMedCrossRefGoogle Scholar
  33. Harrison KJ, Massing B, McKenna C, et al. Molecular cytogenetic analysis of monosomy 7 in pediatric patients with myelodysplastic syndrome. Am J Hematol 1995:48(2):88–91.PubMedCrossRefGoogle Scholar
  34. Chantrain C, Vermylen C, Michaux L, et al. Clonal monosomy 7 and 5q – in a child with myelodysplastic syndrome. Pediatr Hematol Oncol 2000:17(6):505–509.PubMedCrossRefGoogle Scholar
  35. Chakraborty S, Sun CL, Francisco L, et al. Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma. J Clin Oncol 2009:27(5):791–798.PubMedCrossRefGoogle Scholar
  36. Taketani T, Taki T, Takita J, et al. AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies. Genes Chromosomes Cancer 2003:38(1):1–7.PubMedCrossRefGoogle Scholar
  37. Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003:34(2):148–150.PubMedCrossRefGoogle Scholar
  38. Lo Coco F, Pisegna S, Diverio D. The AML1 gene: a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias. Haematologica 1997:82(3):364–370.PubMedGoogle Scholar
  39. Perkins D, Brennan S, Carstairs K, et al. Regional cancer cytogenetics: a report on 1,143 diagnostic cases. Cancer Genet Cytogenet 1997:96(1):64–80.PubMedCrossRefGoogle Scholar
  40. Block AW, Carroll AJ, Hagemeijer A, et al. Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 2002:33(4):401–412.PubMedCrossRefGoogle Scholar
  41. Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 2001:97(1):56–62.PubMedCrossRefGoogle Scholar
  42. Huang ME, Yu-chen Y, Shu-rong C, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988:72:567–572.PubMedGoogle Scholar
  43. Singal R, Ginder GD. DNA methylation. Blood 1999:93(12):4059–4070.PubMedGoogle Scholar
  44. Esteller M, Corn PG, Baylin SB, et al. A gene hypermethylation profile of human cancer. Cancer Res 2001:61(8):3225–3229.PubMedGoogle Scholar
  45. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol 2004:22(22):4632–4642.PubMedCrossRefGoogle Scholar
  46. Vidal DO, Paixao VA, Brait M, et al. Aberrant methylation in pediatric myelodysplastic syndrome. Leuk Res 2007:31(2):175–181.PubMedCrossRefGoogle Scholar
  47. Cameron EE, Bachman KE, Myohanen S, et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999:21: 103–107.PubMedCrossRefGoogle Scholar
  48. Rountree MR, Bachman KE, Herman JG, et al. DNA methylation, chromatin inheritance, and cancer. Oncogene 2001:20(24):3156–3165.PubMedCrossRefGoogle Scholar
  49. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 2000:25(3):269–277.PubMedCrossRefGoogle Scholar
  50. Jones PL, Wolffe AP. Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol 1999:9(5):339–347.PubMedCrossRefGoogle Scholar
  51. Zhou L, Opalinska JB, Sohal DP, et al. Integrative genomic analysis reveals aberrant epigenetic marks in MDS that can be seen in peripheral blood leucocytes. In: Dunbar CE, editor; 2008; San Francisco, CO. American Society of Hematology. p 223.Google Scholar
  52. Kuerbitz SJ, Pahys J, Wilson A, et al. Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia. Carcinogenesis 2002:23(4):559–564.PubMedCrossRefGoogle Scholar
  53. Imamura T, Kakazu N, Hibi S, et al. Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). Genes Chromosomes Cancer 2003:36(4):413–419.PubMedCrossRefGoogle Scholar
  54. Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 1997:90(4):1403–1409.PubMedGoogle Scholar
  55. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999:21(2):163–167.PubMedCrossRefGoogle Scholar
  56. Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009:113(6):1315–1325.PubMedCrossRefGoogle Scholar
  57. 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(10): 3271–3279.PubMedCrossRefGoogle Scholar
  58. Scott SA, Lakshimikuttysamma A, Sheridan DP, et al. Zebularine inhibits human acute myeloid leukemia cell growth in vitro in association with p15INK4B demethylation and reexpression. Exp Hematol 2007:35(2):263–273.PubMedCrossRefGoogle Scholar
  59. Shaker S, Bernstein M, Momparler LF, et al. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2′-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk Res 2003:27(5): 437–444.PubMedCrossRefGoogle Scholar
  60. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006:24(24):3895–3903.PubMedCrossRefGoogle Scholar
  61. Flotho C, Claus R, Batz C, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 2009:23:1019–1028.PubMedCrossRefGoogle Scholar
  62. Kuendgen A, Schmid M, Schlenk R, et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 2006:106(1):112–119.PubMedCrossRefGoogle Scholar
  63. Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 2005:84 Suppl 1:61–66.PubMedCrossRefGoogle Scholar
  64. Rosato RR, Almenara JA, Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 2003:63(13): 3637–3645.PubMedGoogle Scholar
  65. Fouladi M, Furman WL, Chin T, et al. Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children’s Oncology Group report. J Clin Oncol 2006:24(22): 3678–3685.PubMedCrossRefGoogle Scholar
  66. Murgo AJ. Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. Oncologist 2001:6 Suppl 2:22–28.PubMedCrossRefGoogle Scholar
  67. Sekeres MA, List A. Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good? Curr Hematol Rep 2005:4(3):182–185.PubMedGoogle Scholar
  68. Sekeres MA, List A. Immunomodulation in myelodysplastic syndromes. Best Pract Res Clin Haematol 2006:19(4):757–767.PubMedCrossRefGoogle Scholar
  69. Sekeres MA, Maciejewski JP, Giagounidis AA, et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2008:26(36):5943–5949.PubMedCrossRefGoogle Scholar
  70. Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 2006:108(2):618–621.PubMedCrossRefGoogle Scholar
  71. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006:355(14):1456–1465.PubMedCrossRefGoogle Scholar
  72. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008:111(1):86–93.PubMedCrossRefGoogle Scholar
  73. Gilheeney SW, Lyden DC, Sgouros S, et al. A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies. Pediatr Blood Cancer 2007:49(3): 261–265.PubMedCrossRefGoogle Scholar
  74. Kieran MW, Turner CD, Rubin JB, et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 2005:27(11):573–581.PubMedCrossRefGoogle Scholar
  75. Lopez-Aguilar E, Sepulveda-Vildosola AC, Betanzos-Cabrera Y, et al. Phase II study of metronomic chemotherapy with thalidomide, carboplatin-vincristine-fluvastatin in the treatment of brain stem tumors in children. Arch Med Res 2008:39(7):655–662.PubMedCrossRefGoogle Scholar
  76. Rosenfeld C, Cheever MA, Gaiger A. WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Leukemia 2003: 17(7):1301–1312.PubMedCrossRefGoogle Scholar
  77. Boehrer S, Ades L, Braun T, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 2008:111(4):2170–2180.PubMedCrossRefGoogle Scholar
  78. Galili N, Cerny J, Raza A. Current treatment options: impact of cytogenetics on the course of myelodysplasia. Curr Treat Options Oncol 2007:8(2):117–128.PubMedCrossRefGoogle Scholar
  79. 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(7):2302–2308.PubMedCrossRefGoogle Scholar
  80. Fouladi M, Park JR, Sun J, et al. A phase I trial and pharmacokinetic (PK) study of vorinostat (SAHA) in combination with 13 cis-retinoic acid (13cRA) in children with refractory neuroblastomas, medulloblastomas, primitive neuroectodermal tumors (PNETs), and atypical teratoid rhabdoid tumors. In: Grunberg SM, editor; 2008; Chicago, IL. American Society of Clinical Oncology. p 542s.Google Scholar
  81. 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(5): 1591–1600.PubMedCrossRefGoogle Scholar
  82. Weigel BJ, Blaney SM, Reid JM, et al. A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: a Children’s Oncology Group study. Clin Cancer Res 2007:13(6):1789–1793.PubMedCrossRefGoogle Scholar
  83. Bagatell R, Gore L, Egorin MJ, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study. Clin Cancer Res 2007:13(6):1783–1788.PubMedCrossRefGoogle Scholar
  84. Stary J, Locatelli F, Niemeyer CM. Stem cell transplantation for aplastic anemia and myelodysplastic syndrome. Bone Marrow Transplant 2005:35 Suppl 1:S13–S16.PubMedCrossRefGoogle Scholar
  85. Woodard P, Barfield R, Hale G, et al. Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome. Pediatr Blood Cancer 2006:47(7):931–935.PubMedCrossRefGoogle Scholar
  86. Kindwall-Keller T, Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant 2009:43:597–609.PubMedCrossRefGoogle Scholar
  87. Platzbecker U, Mohr B, von Bonin M, et al. Lenalidomide as induction therapy before allogeneic stem cell transplantation in a patient with proliferative CMML-2 and del(5q) not involving the EGR1 locus. Leukemia 2007:21(11):2384–2385.PubMedCrossRefGoogle Scholar
  88. Kroger N. Epigenetic modulation and other options to improve outcome of stem cell transplantation in MDS. San Francisco, CA: American Society of Hematology; 2008.Google Scholar
  89. Reddy P, Maeda Y, Hotary K, et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci USA 2004:101(11):3921–3926.PubMedCrossRefGoogle Scholar
  90. Czibere A, Graef T, Lind J, et al. 5-Azacitidine in combination with donor lymphocyte infusion for treatment of patients with MDS or AML relapsing after allogeneic stem cell transplantation. Blood 2006:108:5341.Google Scholar
  91. Morerio C, Rapella A, Tassano E, et al. Gain of 1q in pediatric myelodysplastic syndromes. Leuk Res 2006:30(11):1437–1441.PubMedCrossRefGoogle Scholar
  92. Mogul MJ, Brady K, Brothman AR, et al. Myelodysplastic syndrome presenting with clonal rearrangement isolated to chromosomal region 1q. Cancer Genet Cytogenet 1997:95(2): 210–212.PubMedCrossRefGoogle Scholar
  93. Lahortiga I, Agirre X, Belloni E, et al. Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells. Oncogene 2004:23(1):311–316.PubMedCrossRefGoogle Scholar
  94. Horsman DE, Massing BG, Chan KW, et al. Unbalanced translocation (1;7) in childhood myelodysplasia. Am J Hematol 1988:27(3):174–178.PubMedCrossRefGoogle Scholar
  95. Stark B, Jeison M, Shohat M, et al. Involvement of 11p15 and 3q21q26 in therapy-related myeloid leukemia (t-ML) in children. Case reports and review of the literature. Cancer Genet Cytogenet 1994:75(1):11–22.PubMedCrossRefGoogle Scholar
  96. Rubin CM, Larson RA, Anastasi J, et al. t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 1990:76(12): 2594–2598.PubMedGoogle Scholar
  97. Dalla Torre CA, de Martino Lee ML, Yoshimoto M, et al. Myelodysplastic syndrome in childhood: report of two cases with deletion of chromosome 4 and the Philadelphia chromosome. Leuk Res 2002:26(6):533–538PubMedCrossRefGoogle Scholar
  98. Pellier I, Le Moine PJ, Rialland X, et al. Myelodysplastic syndrome with t(5;12)(q31;p12-p13) and eosinophilia: a pediatric case with review of literature. J Pediatr Hematol Oncol 1996:18(3): 285–288.PubMedCrossRefGoogle Scholar
  99. Wong WY, Wu SQ. Pentasomy 8 in pediatric myelodysplastic syndrome. Cancer Genet Cytogenet 2000:121(2):220–222.PubMedCrossRefGoogle Scholar
  100. Taki T, Sako M, Tsuchida M, et al. The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood 1997:89(11):3945–3950.PubMedGoogle Scholar
  101. Tosi S, Giudici G, Mosna G, et al. Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Genes Chromosomes Cancer 1998:21(3): 223–229.PubMedCrossRefGoogle Scholar
  102. Coignet LJ, Lima CS, Min T, et al. Myeloid- and lymphoid-specific breakpoint cluster regions in chromosome band 13q14 in acute leukemia. Genes Chromosomes Cancer 1999:25(3): 222–229.PubMedCrossRefGoogle Scholar
  103. Jamal R, Taketani T, Taki T, et al. Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia. Genes Chromosomes Cancer 2001:31(2):187–190.PubMedCrossRefGoogle Scholar
  104. Hellstrom-Lindberg E, Cazzola M. The role of JAK2 mutations in RARS and other MDS. Hematology Am Soc Hematol Educ Program 2008:2008:52–59.CrossRefGoogle Scholar
  105. Side LE, Emanuel PD, Taylor B, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 1998:92(1): 267–272.PubMedGoogle Scholar
  106. Zhang Y, Zhang M, Yang L, et al. NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype. Leuk Res 2007:31(1):109–111.PubMedCrossRefGoogle Scholar
  107. Silveira CG, Oliveira FM, Valera ET, et al. New recurrent deletions in the PPARgamma and TP53 genes are associated with childhood myelodysplastic syndrome. Leuk Res 2009:33(1):19–27.PubMedCrossRefGoogle Scholar
  108. Mahgoub N, Parker RI, Hosler MR, et al. RAS mutations in pediatric leukemias with MLL gene rearrangements. Genes Chromosomes Cancer 1998:21(3):270–275.PubMedCrossRefGoogle Scholar
  109. Gafanovich A, Ramu N, Krichevsky S, et al. Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms. Cancer 1999:85(2):504–510.PubMedCrossRefGoogle Scholar
  110. Kratz CP, Niemeyer CM, Castleberry RP, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 2005:106(6):2183–2185.PubMedCrossRefGoogle Scholar
  111. Bentires-Alj M, Paez JG, David FS, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 2004:64(24):8816–8820.PubMedCrossRefGoogle Scholar
  112. Loh ML, Vattikuti S, Schubbert S, et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004:103(6):2325–2331.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.The University of Colorado Cancer Center and The Center for Cancer and Blood Disorders, The Children’s Hospital, University of Colorado DenverAuroraUSA

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