Original Article

Leukemia (2009) 23, 1490–1499; doi:10.1038/leu.2009.33; published online 5 March 2009

Oncogenes, Fusion Genes and Tumor Suppressor Genes

New insights to the MLL recombinome of acute leukemias

C Meyer1, E Kowarz1, J Hofmann1, A Renneville2,3, J Zuna4, J Trka4, R Ben Abdelali5, E Macintyre5, E De Braekeleer6,7, M De Braekeleer6,7, E Delabesse8, M P de Oliveira9, H Cavé10, E Clappier10, J J M van Dongen11, B V Balgobind12, M M van den Heuvel-Eibrink12, H B Beverloo13, R Panzer-Grümayer14, A Teigler-Schlegel15, J Harbott15, E Kjeldsen16, S Schnittger17, U Koehl18, B Gruhn19, O Heidenreich20, L C Chan21, S F Yip21, M Krzywinski22, C Eckert23, A Möricke24, M Schrappe24, C N Alonso25, B W Schäfer26, J Krauter27, D A Lee28, U zur Stadt29, G Te Kronnie30, R Sutton31, S Izraeli32,33,34, L Trakhtenbrot32,33,34, L Lo Nigro35, G Tsaur36, L Fechina36, T Szczepanski37, S Strehl14, D Ilencikova38, M Molkentin39, T Burmeister39, T Dingermann1, T Klingebiel18 and R Marschalek1

  1. 1Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology, ZAFES, University of Frankfurt, Frankfurt/Main, Germany
  2. 2Department of Hematology, Biology and Pathology Center, CHU of Lille, Lille, France
  3. 3INSERM, U-837, Team 3, Lille, France
  4. 4CLIP, Department of Paediatric Haematology/Oncology, Second Faculty of Medicine, Charles University Prague, Prague, Czech Republic
  5. 5Biological Hematology, AP-HP Necker, UniversitéParis Descartes, Paris, France
  6. 6Faculté de Médecine et des Sciences de la Santé, Laboratoire d'Histologie, Embryologie et Cytogénétique, Université de Bretagne Occidentale, Brest, France
  7. 7INSERM-U613, Brest, France
  8. 8CHU Purpan, Laboratoire d'Hématologie, Toulouse, France
  9. 9Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil
  10. 10Département de Génétique, Hopital Robert Debré, Paris, France
  11. 11Department of Immunology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
  12. 12Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
  13. 13Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
  14. 14Children's Cancer Research Institute, Vienna, Austria
  15. 15Department of Pediatric Hematology and Oncology, Children's University Hospital, Giessen, Germany
  16. 16Cancercytogenetics Laboratory, Aarhus University Hospital, Aarhus, Denmark
  17. 17MLL Munich Leukemia Laboratory, Munich, Germany
  18. 18Department of Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany
  19. 19Department of Pediatrics, University of Jena, Jena, Germany
  20. 20Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
  21. 21Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
  22. 22Canada's Michael Smith Genome Sciences Center, Vancouver, British Columbia, Canada
  23. 23Department of Pediatric Oncology and Hematology, Charité Medical University Berlin, CVK, Berlin, Germany
  24. 24Department of Paediatrics, University of Schleswig-Holstein, Kiel, Germany
  25. 25Servcio de Hemato-Oncología, Hospital Nacional de Pediatría Prof Dr JP Garrahan, Buenos Aires, Argentina
  26. 26Department of Oncology, University Children's Hospital, Zurich, Switzerland
  27. 27Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hanover Medical School, Hanover, Germany
  28. 28Division of Pediatrics, Cell Therapy Section, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  29. 29Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  30. 30Department of Paediatrics and Oncohematology, University of Padua, Padua, Italy
  31. 31Sydney Children's Hospital, Children's Cancer Institute, Sydney, New South Wales, Australia
  32. 32Department of Pediatric Hemato-Oncology, The Chaim Sheba Medical Center, Tel Aviv, Israel
  33. 33The Cancer Research Center, Tel Aviv, Israel
  34. 34Sackler Medical School Tel Aviv University, Tel Aviv, Israel
  35. 35Center of Pediatric Hematology Oncology, University of Catania, Catania, Italy
  36. 36Regional Children Hospital 1, Pediatric Oncology and Hematology Center, Research Institute of Medical Cell Technologies, Ekaterinburg, Russia
  37. 37Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland
  38. 38Department of Clinical Genetics, National Cancer Hospital, Bratislava, Slovakia
  39. 39Medical Faculty III, CBF, Charité Medical University Berlin, Berlin, Germany

Correspondence: Professor Dr R Marschalek, Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology, ZAFES, University of Frankfurt, Max-von-Laue-Str. 9, Frankfurt/Main D-60438, Germany. E-mail: Rolf.Marschalek@em.uni-frankfurt.de

Received 9 December 2008; Revised 15 January 2009; Accepted 28 January 2009; Published online 5 March 2009.

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Abstract

Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.

Keywords:

MLL, translocations partner genes, acute leukemia, ALL, AML