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Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

Abstract

Alternative genetic pathways were previously outlined in the pathogenesis of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) based on cytogenetic characteristics. Some of the chromosome aberrations, the recurrent balanced translocations or inversions, directly result in chimeric rearrangement of genes for hematopoietic transcription factors (class II mutations) which disturb cellular differentiation. Other genetic abnormalities in t-MDS and t-AML comprise activating point mutations or internal tandem duplications of genes involved in signal transduction as tyrosine kinase receptors or genes more downstream in the RAS-BRAF pathway (class I mutations). The alternative genetic pathways of t-MDS and t-AML can now be further characterized by a different clustering of six individual class I mutations and mutations of AML1 and p53 in the various pathways. In addition, there is a significant association between class I and class II mutations possibly indicating cooperation in leukemogenesis, and between mutations of AML1 and RAS related to subsequent progression from t-MDS to t-AML. Therapy-related and de novo myelodysplasia and acute myeloid leukemia seem to share genetic pathways, and surprisingly gene mutations were in general not more frequent in patients with t-MDS or t-AML as compared to similar cases of de novo MDS and AML studied previously.

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References

  1. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1, 612 patients entered into the MRC AML 10 trial. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  2. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000; 96: 4075–4083.

    CAS  PubMed  Google Scholar 

  3. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.

    Article  CAS  PubMed  Google Scholar 

  4. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  5. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P . Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood 1995; 86: 3542–3552.

    CAS  PubMed  Google Scholar 

  6. Mauritzson N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia 2002; 12: 2366–2378.

    Article  Google Scholar 

  7. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003; 102: 43–52.

    Article  CAS  PubMed  Google Scholar 

  8. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C . Genetic pathways in therapy-related myelodysplasia in acute myeloid leukemia. Blood 2002; 99: 1909–1912.

    Article  CAS  PubMed  Google Scholar 

  9. Deguchi K, Gilliland DG . Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML. Leukemia 2002; 16: 740–744.

    Article  CAS  PubMed  Google Scholar 

  10. Kelly LM, Gilliland DG . Genetics of myeloid leukemias. Ann Rev Genomics Hum Genet 2002; 3: 179–198.

    Article  CAS  Google Scholar 

  11. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 2001; 19: 1405–1413.

    Article  CAS  PubMed  Google Scholar 

  12. Christiansen DH, Pedersen-Bjergaard J . Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. Leukemia 2001; 15: 1848–1851.

    Article  CAS  PubMed  Google Scholar 

  13. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 2004; 104: 1474–1481.

    Article  CAS  PubMed  Google Scholar 

  14. Christiansen DH, Desta F, Andersen MK, Pedersen-Bjergaard J . Mutation of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF – signal transduction pathway in therapy related myelodysplasia and acute myeloid leukaemia. Leukemia 2005; 19: 2232–2240.

    Article  CAS  PubMed  Google Scholar 

  15. Christiansen DH, Desta F, Andersen MK, Pedersen-Bjergaard J . Mutation of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations. (submitted).

  16. Desta F, Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Activating JAK2V617F mutations are uncommom in therapy-related MDS and AML and observed in atypic cases. Leukemia 2006; 20: 547–548.

    Article  CAS  PubMed  Google Scholar 

  17. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukaemia. Leukemia 2003; 17: 1813–1819.

    Article  CAS  PubMed  Google Scholar 

  18. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T . Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 2003; 101: 673–680.

    Article  CAS  PubMed  Google Scholar 

  19. Andersen MK, Christiansen DH, Pedersen-Bjergaard J . Centromeric breakage and highly rearranged chromosome derivatives associated with mutation of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents. An M-Fish study. Genes Chromosomes Cancer 2005; 42: 358–371.

    Article  CAS  PubMed  Google Scholar 

  20. Andersen MK, Christiansen DH, Kirchhoff M, Pedersen-Bjergaard J . Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents. Genes, Chromosomes Cancer 2001; 31: 33–41.

    Article  CAS  PubMed  Google Scholar 

  21. Andersen MK, Christiansen DH, Pedersen-Bjergaard J . Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML. Leukemia 2005; 19: 197–200.

    Article  CAS  PubMed  Google Scholar 

  22. Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T . Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized bi genomic imbalances and a specific gene expression profile. Leukemia 2005; 43: 227–238.

    CAS  Google Scholar 

  23. Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM . Expression profiling of CD34+ hematopoietic stem/progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc Natl Acad Sci USA 2002; 99: 14925–14930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ratain MJ, Kaminer LS, Bitran JD, Larson RA, Le Beau MM, Skosey C et al. Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 1987; 70: 1412–1417.

    CAS  PubMed  Google Scholar 

  25. Pui CH, Behm FG, Raimondi SC, Dodge RK, George SL, Rivera GK et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 1989; 321: 136–142.

    Article  CAS  PubMed  Google Scholar 

  26. Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB . Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. Leukemia 1998; 12: 840–844.

    Article  CAS  PubMed  Google Scholar 

  27. Bloomfield CD, Archer KJ, Mrózek K, Lilington DM, Kaneko Y, Head DR et al. 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: Report from an international workshop. Genes, Chromosomes Cancer 2002; 33: 362–378.

    Article  PubMed  Google Scholar 

  28. Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ . Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci USA 1988; 85: 1629–1633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Meshinchi S, Stirewalt DL, Alonzo TA, Zhang Q, Sweetser DA, Woods WG et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 2003; 102: 1474–1479.

    Article  CAS  PubMed  Google Scholar 

  30. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K, Groves MJ et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 2005; 106: 2113–2119.

    Article  CAS  PubMed  Google Scholar 

  31. Quesnel B, Kantarjian H, Pedersen-Bjergaard J, Brault P, Estey E, Lai JL et al. Therapy-related acute myeloid leukemia with t(8;21), inv(16) and t(8;16): a report on 25 cases and review of the literature. J Clin Oncol 1993; 11: 2370–2379.

    Article  CAS  PubMed  Google Scholar 

  32. Pedersen-Bjergaard J, Andersen MK, Johansson B . Balanced chromosome aberrations in leukemias following chemotherapy with DNA – topoisomerase II inhibitors. J Clin Oncol 1998; 16: 1897–1898.

    Article  CAS  PubMed  Google Scholar 

  33. Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R . 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: Report from an international workshop. Genes, Chromosomes Cancer 2002; 33: 379–394.

    Article  PubMed  Google Scholar 

  34. Gari M, Goodeve A, Wilson G, Winship P, Langabeer S, Linch D et al. c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br J Haematol 1999; 105: 894–900.

    Article  CAS  PubMed  Google Scholar 

  35. Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E et al. C-kit mutations in core binding factor leukemias. Blood 2000; 95: 726–727.

    CAS  PubMed  Google Scholar 

  36. Care RS, Valk PJ, Goodeve AC, Abu-Duhier FM, Geertsma-Kleinekoort WM, Wilson GA et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol 2003; 121: 775–777.

    Article  CAS  PubMed  Google Scholar 

  37. Detourmignies L, Castaigne S, Stoppa AM, Harousseau JL, Sadoun A, Janvier M et al. Therapy-related acute promyelocytic leukemia: A report on 16 cases. J Clin Oncol 1992; 10: 1430–1435.

    Article  CAS  PubMed  Google Scholar 

  38. Carli PM, Sgro C, Parchin-Geneste N, Isambert N, Mugneret F, Girodon F et al. Increase therapy-related leukemia secondary to breast cancer. Leukemia 2000; 14: 1014–1017.

    Article  CAS  PubMed  Google Scholar 

  39. Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 2005; 352: 1529–1538.

    Article  CAS  PubMed  Google Scholar 

  40. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752–1759.

    Article  CAS  PubMed  Google Scholar 

  41. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    Article  CAS  PubMed  Google Scholar 

  42. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. 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 2002; 100: 59–66.

    Article  CAS  PubMed  Google Scholar 

  43. Borrow J, Shearman AM, Stanton Jr VP, Becher R, Collins T, Williams AJ et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996; 12: 159–167.

    Article  CAS  PubMed  Google Scholar 

  44. Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997; 89: 3936–3944.

    CAS  PubMed  Google Scholar 

  45. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD . NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res 1998; 58: 4269–4273.

    CAS  PubMed  Google Scholar 

  46. Nakamura T, Yamazaki Y, Hatano Y, Miura I . NUP98 is fused to PMXI homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999; 94: 741–747.

    CAS  PubMed  Google Scholar 

  47. Ahuja HG, Felix CA, Aplan PD . The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999; 94: 3258–3261.

    CAS  PubMed  Google Scholar 

  48. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood 1999; 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  49. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

    Article  CAS  PubMed  Google Scholar 

  50. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    Article  CAS  PubMed  Google Scholar 

  51. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005; 106: 1207–1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

    Article  CAS  PubMed  Google Scholar 

  53. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–4020.

    Article  CAS  PubMed  Google Scholar 

  54. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 1998; 58: 55–59.

    CAS  PubMed  Google Scholar 

  55. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identity a prognostically unfavourable subset of AML. Leukemia 2000; 14: 796–804.

    Article  CAS  PubMed  Google Scholar 

  56. Pedersen-Bjergaard J . Insights into leukemogenesis from therapy-related leukemia. New Engl J Med 2005; 352: 1591–1594.

    Article  CAS  PubMed  Google Scholar 

  57. Felix CA, Lange BJ, Hosler MR, Fertala J, Bjornsti MA . Chromosome band 11q23 translocation breakpoints are DNA topoisomerase II cleavage sites. Cancer Res 1995; 55: 4287–4292.

    CAS  PubMed  Google Scholar 

  58. Stanulla M, Wang J, Chervinsky DS, Thandla S, Aplan PD . DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during initial stages of apoptosis. Mol Cell Biol 1997; 17: 4070–4079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Strissel PL, Strick R, Rowley JD, Zeleznik-Le NJ . An in vivo topoisomerase II cleavage site and a Dnase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Blood 1998; 92: 3793–3803.

    CAS  PubMed  Google Scholar 

  60. Ahuja HG, Felix CA, Aplan PD . Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Genes Chromosomes Cancer 2000; 29: 96–105.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang Y, Strissel P, Strick R, Chen J, Nucifora G, Le Beau MM et al. Genomic DNA breakpoints in AML1/RUNXI and ETO cluster with topoisomerase II DNA cleavage and Dnase I hypersensitive sites in t(8;21) leukemia. Proc NatlAcad Sci USA 2002; 99: 3070–3075.

    Article  CAS  Google Scholar 

  62. Libura M, Asnafi V, Tu A, Delabesse E, Tigaud I, Cymballista F et al. FLT3 and MLL intragenic abnormalities in AML reflect a common catogery of genotoxic stress. Blood 2003; 102: 2198–2204.

    Article  CAS  PubMed  Google Scholar 

  63. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukaemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003; 34: 148–150.

    Article  CAS  PubMed  Google Scholar 

  64. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004; 103: 2325–2331.

    Article  CAS  PubMed  Google Scholar 

  65. Thiede C, Steudel C, Schäkel U, Ehninger G . Mutations of the SHP-2 protein tyrosine phosphatase in adult patients with acute myeloid leukemia. Blood 2004; 104: 165a Abstract 572.

    Google Scholar 

  66. Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 2004; 104: 307–313.

    Article  CAS  PubMed  Google Scholar 

  67. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595.

    Article  CAS  PubMed  Google Scholar 

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Pedersen-Bjergaard, J., Christiansen, D., Desta, F. et al. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 20, 1943–1949 (2006). https://doi.org/10.1038/sj.leu.2404381

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