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Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

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Abstract

Childhood acute lymphoblastic leukemia (ALL) is caused by malignant immature lymphocytes. Even though childhood ALL can be cured in a large number of patients, around 20% of the patients suffer a relapse after chemotherapy. The origin of the relapse is unclear at the present time. Given the high plasticity of cells, we searched for leukemia-associated genetic aberrations and immunoglobulin (IG) gene rearrangements in mesenchymal stem cells (MSC) from childhood B-cell precursor ALL patients. MSC from all ten ALL patients analyzed presented the chromosomal translocations that had been detected in leukemia cells (TEL-AML1, E2A-PBX1, or MLL rearrangement). The proportions of translocation-positive MSC varied between 10% and 54% depending on the patients and the time point of analysis. Leukemia-specific IG gene rearrangements were detected in the MSC from three ALL patients. The detection of leukemia-associated genetic aberrations in MSC indicates a clonal relationship between MSC and leukemia cells and suggests their involvement in the pathogenesis and/or pathophysiology of childhood ALL.

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References

  1. Pui CH, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166–178

    Article  CAS  PubMed  Google Scholar 

  2. Gaynon PS (2005) Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 131:579–587

    Article  PubMed  Google Scholar 

  3. Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3:639–649

    Article  CAS  PubMed  Google Scholar 

  4. Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K, Strombeck B, Garwicz S, Bekassy AN, Schmiegelow K, Lausen B, Hokland P, Lehmann S, Juliusson G, Johansson B, Jacobsen SE (2005) Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 11:630–637

    Article  CAS  PubMed  Google Scholar 

  5. Hotfilder M, Rottgers S, Rosemann A, Schrauder A, Schrappe M, Pieters R, Jurgens H, Harbott J, Vormoor J (2005) Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+ CD19− cells. Cancer Res 65:1442–1449

    Article  CAS  PubMed  Google Scholar 

  6. Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A (2009) Expression of CD133 on leukemia-initiating cells in childhood ALL. Blood 113:3287–3296

    Article  CAS  PubMed  Google Scholar 

  7. Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G, Gabl C, Dirnhofer S, Clausen J, Gastl G (2000) Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 355:1688–1691

    Article  CAS  PubMed  Google Scholar 

  8. Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S, Green J, Colman S, Piacibello W, Buckle V, Tsuzuki S, Greaves M, Enver T (2008) Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319:336–339

    Article  CAS  PubMed  Google Scholar 

  9. Nagasawa T (2006) Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 6:107–116

    Article  CAS  PubMed  Google Scholar 

  10. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  CAS  PubMed  Google Scholar 

  11. Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74

    Article  CAS  PubMed  Google Scholar 

  12. Mueller LP, Luetzkendorf J, Mueller T, Reichelt K, Simon H, Schmoll HJ (2006) Presence of mesenchymal stem cells in human bone marrow after exposure to chemotherapy: evidence of resistance to apoptosis induction. Stem Cells 24:2753–2765

    Article  CAS  PubMed  Google Scholar 

  13. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49

    Article  CAS  PubMed  Google Scholar 

  14. Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M, Creyghton MP, Steine EJ, Cassady JP, Foreman R, Lengner CJ, Dausman JA, Jaenisch R (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133:250–264

    Article  CAS  PubMed  Google Scholar 

  15. Cobaleda C, Jochum W, Busslinger M (2007) Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449:473–477

    Article  CAS  PubMed  Google Scholar 

  16. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  CAS  PubMed  Google Scholar 

  17. Beishuizen A, Verhoeven MA, van Wering ER, Hahlen K, Hooijkaas H, van Dongen JJ (1994) Analysis of Ig and T-cell receptor genes in 40 childhood acute lymphoblastic leukemias at diagnosis and subsequent relapse: implications for the detection of minimal residual disease by polymerase chain reaction analysis. Blood 83:2238–2247

    CAS  PubMed  Google Scholar 

  18. Gimble JM, Robinson CE, Wu X, Kelly KA (1996) The function of adipocytes in the bone marrow stroma: an update. Bone 19:421–428

    Article  CAS  PubMed  Google Scholar 

  19. Estrov Z, Talpaz M, Zipf TF, Kantarjian HM, Ku S, Ouspenskaia MV, Hirsch-Ginsberg C, Huh Y, Yee G, Kurzrock R (1996) Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181). J Cell Physiol 166:618–630

    Article  CAS  PubMed  Google Scholar 

  20. Thalmeier K, Meissner P, Reisbach G, Hultner L, Mortensen BT, Brechtel A, Oostendorp RA, Dormer P (1996) Constitutive and modulated cytokine expression in two permanent human bone marrow stromal cell lines. Exp Hematol 24:1–10

    CAS  PubMed  Google Scholar 

  21. Li LP, Schlag PM, Blankenstein T (1997) Transient expression of SV 40 large T antigen by Cre/LoxP-mediated site-specific deletion in primary human tumor cells. Hum Gene Ther 8:1695–1700

    Article  CAS  PubMed  Google Scholar 

  22. Martin-Subero JI, Chudoba I, Harder L, Gesk S, Grote W, Novo FJ, Calasanz MJ, Siebert R (2002) Multicolor-FICTION: expanding the possibilities of combined morphologic, immunophenotypic, and genetic single cell analyses. Am J Pathol 161:413–420

    CAS  PubMed  Google Scholar 

  23. Pongers-Willemse MJ, Seriu T, Stolz F, d'Aniello E, Gameiro P, Pisa P, Gonzalez M, Bartram CR, Panzer-Grumayer ER, Biondi A, San Miguel JF, van Dongen JJ (1999) Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: report of the BIOMED-1 CONCERTED ACTION: investigation of minimal residual disease in acute leukemia. Leukemia 13:110–118

    Article  CAS  PubMed  Google Scholar 

  24. Szczepanski T, van der Velden VH, Hoogeveen PG, de Bie M, Jacobs DC, van Wering ER, van Dongen JJ (2004) Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells. Blood 103:3798–3804

    Article  CAS  PubMed  Google Scholar 

  25. Taube T, Seeger K, Beyermann B, Hanel C, Duda S, Linderkamp C, Henze G (1997) Multiplex PCR for simultaneous detection of the most frequent T cell receptor-delta gene rearrangements in childhood ALL. Leukemia 11:1978–1982

    Article  CAS  PubMed  Google Scholar 

  26. Bottaro M, Berti E, Biondi A, Migone N, Crosti L (1994) Heteroduplex analysis of T-cell receptor gamma gene rearrangements for diagnosis and monitoring of cutaneous T-cell lymphomas. Blood 83:3271–3278

    CAS  PubMed  Google Scholar 

  27. Eckert C, Landt O (2004) Real-time PCR to detect minimal residual disease in childhood ALL. Methods Mol Med 91:175–182

    CAS  PubMed  Google Scholar 

  28. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diaz MG, Malec M, Langerak AW, San Miguel JF, Biondi A (1999) Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 13:1901–1928

    Article  PubMed  Google Scholar 

  29. van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER, Flohr T, Sutton R, Cave H, Madsen HO, Cayuela JM, Trka J, Eckert C, Foroni L, Zur Stadt U, Beldjord K, Raff T, van der Schoot CE, van Dongen JJ (2007) Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 21:604–611

    PubMed  Google Scholar 

  30. Massenkeil G, Nagy M, Lawang M, Rosen O, Genvresse I, Geserick G, Dorken B, Arnold R (2003) Reduced intensity conditioning and prophylactic DLI can cure patients with high-risk acute leukaemias if complete donor chimerism can be achieved. Bone Marrow Transplant 31:339–345

    Article  CAS  PubMed  Google Scholar 

  31. Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, den Boer ML, Pieters R, Ennas MG, Angelucci E, Koehl U, Greil J, Griesinger F, Zur Stadt U, Eckert C, Szczepanski T, Niggli FK, Schafer BW, Kempski H, Brady HJ, Zuna J, Trka J, Nigro LL, Biondi A, Delabesse E, Macintyre E, Stanulla M, Schrappe M, Haas OA, Burmeister T, Dingermann T, Klingebiel T, Marschalek R (2006) The MLL recombinome of acute leukemias. Leukemia 20:777–784

    Article  CAS  PubMed  Google Scholar 

  32. Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG, Nishikawa S (2007) Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129:1377–1388

    Article  CAS  PubMed  Google Scholar 

  33. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67:9142–9149

    Article  CAS  PubMed  Google Scholar 

  34. Harrison CJ (2001) The detection and significance of chromosomal abnormalities in childhood acute lymphoblastic leukaemia. Blood Rev 15:49–59

    Article  CAS  PubMed  Google Scholar 

  35. Masramon L, Vendrell E, Tarafa G, Capella G, Miro R, Ribas M, Peinado MA (2006) Genetic instability and divergence of clonal populations in colon cancer cells in vitro. J Cell Sci 119:1477–1482

    Article  CAS  PubMed  Google Scholar 

  36. Kamps MP, Look AT, Baltimore D (1991) The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev 5:358–368

    Article  CAS  PubMed  Google Scholar 

  37. Di Rocco G, Mavilio F, Zappavigna V (1997) Functional dissection of a transcriptionally active, target-specific Hox-Pbx complex. Embo J 16:3644–3654

    Article  PubMed  Google Scholar 

  38. Meyer C, Schneider B, Reichel M, Angermueller S, Strehl S, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, Pieters R, Haas OA, Dingermann T, Klingebiel T, Marschalek R (2005) Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci U S A 102:449–454

    Article  CAS  PubMed  Google Scholar 

  39. Streubel B, Chott A, Huber D, Exner M, Jager U, Wagner O, Schwarzinger I (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259

    Article  CAS  PubMed  Google Scholar 

  40. Hentel J, Hirschhorn K (1971) The origin of some bone marrow fibroblasts. Blood 38:81–86

    CAS  PubMed  Google Scholar 

  41. Greenberg BR, Wilson FD, Woo L, Jenks HM (1978) Cytogentics of fibroblastic colonies in Ph1-positive chronic myelogenous leukemia. Blood 51:1039–1044

    CAS  PubMed  Google Scholar 

  42. Zhao Z, Tang X, You Y, Li W, Liu F, Zou P (2006) Assessment of bone marrow mesenchymal stem cell biological characteristics and support hemotopoiesis function in patients with chronic myeloid leukemia. Leuk Res 30:993–1003

    Article  CAS  PubMed  Google Scholar 

  43. Gale KB, Ford AM, Repp R, Borkhardt A, Keller C, Eden OB, Greaves MF (1997) Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci U S A 94:13950–13954

    Article  CAS  PubMed  Google Scholar 

  44. Wagers AJ, Weissman IL (2004) Plasticity of adult stem cells. Cell 116:639–648

    Article  CAS  PubMed  Google Scholar 

  45. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545

    Article  CAS  PubMed  Google Scholar 

  46. Ehnfors J, Kost-Alimova M, Persson NL, Bergsmedh A, Castro J, Levchenko-Tegnebratt T, Yang L, Panaretakis T, Holmgren L (2009) Horizontal transfer of tumor DNA to endothelial cells in vivo. Cell Death Differ 16:749–757

    Article  CAS  PubMed  Google Scholar 

  47. Holmgren L, Szeles A, Rajnavolgyi E, Folkman J, Klein G, Ernberg I, Falk KI (1999) Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood 93:3956–3963

    CAS  PubMed  Google Scholar 

  48. Pozzobon M, Piccoli M, Ditadi A, Bollini S, Destro R, Andre-Schmutz I, Masiero L, Lenzini E, Zanesco L, Petrelli L, Cavazzana-Calvo M, Gazzola MV, De Coppi P (2009) Mesenchymal stromal cells can be derived from bone marrow CD133+ cells: implications for therapy. Stem Cells Dev 18:497–510

    Article  CAS  PubMed  Google Scholar 

  49. O'Neil J, Look AT (2007) Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 26:6838–6849

    Article  PubMed  Google Scholar 

  50. Callen E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M, Nussenzweig A (2007) ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 130:63–75

    Article  CAS  PubMed  Google Scholar 

  51. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR (2008) BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453:110–114

    Article  CAS  PubMed  Google Scholar 

  52. Vanura K, Montpellier B, Le T, Spicuglia S, Navarro JM, Cabaud O, Roulland S, Vachez E, Prinz I, Ferrier P, Marculescu R, Jager U, Nadel B (2007) In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability. PLoS Biol 5:e43

    Article  PubMed  Google Scholar 

  53. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–764

    Article  CAS  PubMed  Google Scholar 

  54. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, Downing JR (2008) Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322:1377–1380

    Article  CAS  PubMed  Google Scholar 

  55. Duesberg PH (2003) Are cancers dependent on oncogenes or on aneuploidy? Cancer Genet Cytogenet 143:89–91

    Article  CAS  PubMed  Google Scholar 

  56. Izraeli S (2006) Perspective: chromosomal aneuploidy in leukemia—lessons from down syndrome. Hematol Oncol 24:3–6

    Article  CAS  PubMed  Google Scholar 

  57. Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432:338–341

    Article  CAS  PubMed  Google Scholar 

  58. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, Wilhelm JS, Zheng Y, Cancelas JA, Gu Y, Jansen M, Dimartino JF, Mulloy JC (2008) Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13:483–495

    Article  CAS  PubMed  Google Scholar 

  59. Garayoa M, Garcia JL, Santamaria C, Garcia-Gomez A, Blanco JF, Pandiella A, Hernandez JM, Sanchez-Guijo FM, Del Canizo MC, Gutierrez NC, San Miguel JF (2009) Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia 23:1515–1527

    Article  CAS  PubMed  Google Scholar 

  60. Lopez-Villar O, Garcia JL, Sanchez-Guijo FM, Robledo C, Villaron EM, Hernandez-Campo P, Lopez-Holgado N, Diez-Campelo M, Barbado MV, Perez-Simon JA, Hernandez-Rivas JM, San-Miguel JF, del Canizo MC (2009) Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q-syndrome. Leukemia 23:664–672

    Article  CAS  PubMed  Google Scholar 

  61. Borgmann A, Zinn C, Hartmann R, Herold R, Kaatsch P, Escherich G, Moricke A, Henze G, von Stackelberg A (2008) Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44:257–268

    Article  PubMed  Google Scholar 

  62. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O (2007) Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11:421–429

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to S. Tuerkmen for metaphase analysis and M. Nagy for chimerism analysis and to R. Marschalek for MLL sequence analysis. We thank the staff members of the ALL-REZ BFM study group, Shidokht Shalapour, T. Schüler, and L. Bastian for their support. This work was supported by the DFG Sonderforschungsbereich TR 36 and the Deutsche Krebshilfe (Bonn, Germany).

Authorship

Contribution: S.S. designed, performed, analyzed experiments, and wrote the manuscript; T.B. designed, analyzed experiments, and wrote the manuscript; T.K. analyzed experiments and wrote the manuscript; C.E. and M.P. performed experiments; and C.E. and J.P. analyzed experiments and wrote the manuscript. G.H. coordinates the ALL-relapse-BFM study; K.S. and G.H. collected clinical data used in this study and analyzed data.

Conflict of interest disclosure

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353, Berlin, Germany

    Shabnam Shalapour, Cornelia Eckert, Karl Seeger, Madlen Pfau, Javier Prada & Günter Henze

  2. Institute of Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin-Franklin, 12200, Berlin, Germany

    Shabnam Shalapour, Thomas Blankenstein & Thomas Kammertoens

  3. Max-Delbrück Center for Molecular Medicine, Robert-Roessle Strasse 10, 13122, Berlin, Germany

    Thomas Blankenstein & Thomas Kammertoens

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  1. Shabnam Shalapour
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  2. Cornelia Eckert
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  3. Karl Seeger
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Correspondence to Shabnam Shalapour or Thomas Blankenstein.

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T. B. and T. K. contributed equally to this work.

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Shalapour, S., Eckert, C., Seeger, K. et al. Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia. J Mol Med 88, 249–265 (2010). https://doi.org/10.1007/s00109-009-0583-8

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