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    Leukemia. 2017 Jul 13. pii: leu2017213. doi: 10.1038/leu.2017.213
    The MLL recombinome of acute leukemias in 2017.
    Meyer C1,  Burmeister T2,  Gröger D3,  Tsaur G4,  Fechina L5,  Renneville S6,  Sutton R7,  Venn NC8,  Emerenciano M9,  Pombo-de-Oliveira MS10,  Barbieri Blunck C11,  Almeida Lopes B12,  Zuna J13,  Trka J14,  Ballerini P15,  Lapillonne H16,  De Braekeleer M17,  Cazzaniga G18,  Corral Abascal L19,  van der Velden VHJ20,  Delabesse E21,  Park TS22,  Oh SH23,  Silva MLM24,  Lund-Aho T25,  Juvonen V26,  Moore AS27,  Heidenreich O28,  Vormoor J29,  Zerkalenkova E30,  Olshanskaya Y31,  Bueno C32,  Menendez P33,  Teigler-Schlegel S34,  Zur Stadt U35,  Lentes J36,  Göhring G37,  Kustanovich S38,  Aleinikova O39,  Schäfer BW40,  Kubetzko S41,  Madsen HO42,  Gruhn B43,  Duarte X44,  Gameiro P45,  Lippert E46,  Bidet S47,  Cayuela JM48,  Clappier E49,  Alonso CN50,  Zwaan CM51,  van den Heuvel-Eibrink MM52,  Izraeli S53,  Trakhtenbrot L54,  Archer P55,  Hancock J56,  Möricke A57,  Alten J58,  Schrappe M59,  Stanulla M60,  Strehl S61,  Attarbaschi A62,  Dworzak M63,  Haas OA64,  Panzer-Grümayer R65,  Sedék L66,  Szczepański T67,  Caye S68,  Suarez L69,  Cavé H70,  Marschalek R71
    Author information
    1Institute of Pharm. Biology/DCAL, Goethe-University, Frankfurt/Main, Germany.
    2Charité-Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany.
    3Charité-Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany.
    4Regional Children Hospital 1, Research Institute of Medical Cell Technologies, Pediatric Oncology and Hematology Center, Ural Federal University named after the first President of Russia BN Yeltsin, Ekaterinburg, Russia.
    5Regional Children Hospital 1, Research Institute of Medical Cell Technologies, Pediatric Oncology and Hematology Center, Ural Federal University named after the first President of Russia BN Yeltsin, Ekaterinburg, Russia.
    6Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille; INSERM, UMR-S 1172, Cancer Research Institute of Lille, Lille, France.
    7Children's Cancer Institute Australia, Uinversity of NSW Sydney, Australia.
    8Children's Cancer Institute Australia, Uinversity of NSW Sydney, Australia.
    9Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil.
    10Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil.
    11Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil.
    12Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil.
    13CLIP, Department of Paediatric Haematology/Oncology, Charles University Prague, 2nd Faculty of Medicine, Prague, Czech Republic.
    14CLIP, Department of Paediatric Haematology/Oncology, Charles University Prague, 2nd Faculty of Medicine, Prague, Czech Republic.
    15Biological Hematology, AP-HP A. Trousseau, Pierre et Marie Curie University, Paris, France.
    16Biological Hematology, AP-HP A. Trousseau, Pierre et Marie Curie University, Paris, France.
    17Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Laboratoire d'Histologie, Embryologie et Cytogénétique &INSERM-U1078, Brest, France.
    18Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Monza, Italy.
    19Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Monza, Italy.
    20Erasmus MC, Department of Immunology, Rotterdam, The Netherlands.
    21CHU Purpan, Laboratoire d'Hématologie, Toulouse, France.
    22Department of Laboratory Medicine, School of Medicine, Kyung Hee University, Seoul, Korea.
    23Department of Laboratory Medicine, Inje University College of Medicine, Busan, Korea.
    24Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute (INCA), Rio de Janeiro, Brazil.
    25Laboratory of Clinical Genetics, Fimlab Laboratories, Tampere, Finland.
    26Department of Clinical Chemistry and TYKSLAB, University of Turku and Turku University Central Hospital, Turku, Finland.
    27The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia.
    28Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
    29Northern Institute for Cancer Research, Newcastle University and the Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
    30National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev, Moscow.
    31National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev, Moscow.
    32Josep Carreras Leukemia Research Institute. Department of Biomedicine-School of Medicine, University of Barcelona. CIBER de Cancer (CIBERONC), ISCIII, Madrid. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
    33Josep Carreras Leukemia Research Institute. Department of Biomedicine-School of Medicine, University of Barcelona. CIBER de Cancer (CIBERONC), ISCIII, Madrid. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
    34Department of Experimental Pathology and Cytology, Institute of Pathology, Giessen, Germany.
    35Center for Diagnostic, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
    36Department of Human Genetics, Hannover Medical School, Hanover, Germany.
    37Department of Human Genetics, Hannover Medical School, Hanover, Germany.
    38Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus.
    39Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus.
    40University Children's Hospital Zurich, Department of Oncology, Zurich, Switzerland.
    41University Children's Hospital Zurich, Department of Oncology, Zurich, Switzerland.
    42Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark.
    43Department of Pediatrics, Jena University Hospital, Jena, Germany.
    44Department of Pediatrics, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal.
    45Hemato-Oncology Laboratory, UIPM, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal.
    46Hématologie Biologique, CHU de Brest and INSERM U1078, Université de Bretagne Occidentale, Brest, France.
    47Hématologie Biologique, CHU de Brest and INSERM U1078, Université de Bretagne Occidentale, Brest, France.
    48Laboratoire d'hématologie, AP-HP Saint-Louis, Paris Diderot University, Paris, France.
    49Laboratoire d'hématologie, AP-HP Saint-Louis, Paris Diderot University, Paris, France.
    50Hospital Nacional de Pediatría Prof Dr J. P. Garrahan, Servcio de Hemato-Oncología, Buenos Aires, Argentina.
    51Erasmus MC, Sophia Children's Hospital, Department of Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
    52Erasmus MC, Sophia Children's Hospital, Department of Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
    53The Chaim Sheba Medical Center, Department of Pediatric Hemato-Oncology and the Cancer Research Center, and Sackler Medical School Tel Aviv University, Tel Aviv, Israel.
    54The Chaim Sheba Medical Center, Department of Pediatric Hemato-Oncology and the Cancer Research Center, and Sackler Medical School Tel Aviv University, Tel Aviv, Israel.
    55Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bristol NHS Trust, Bristol, UK.
    56Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bristol NHS Trust, Bristol, UK.
    57Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
    58Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
    59Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
    60Department of Pediatrics, MHH, Hanover, Germany.
    61Children's Cancer Research Institute and St Anna Children's Hospital, Dept. of Pediatrics, Medical University of Vienna, Vienna, Austria.
    62Children's Cancer Research Institute and St Anna Children's Hospital, Dept. of Pediatrics, Medical University of Vienna, Vienna, Austria.
    63Children's Cancer Research Institute and St Anna Children's Hospital, Dept. of Pediatrics, Medical University of Vienna, Vienna, Austria.
    64Children's Cancer Research Institute and St Anna Children's Hospital, Dept. of Pediatrics, Medical University of Vienna, Vienna, Austria.
    65Children's Cancer Research Institute and St Anna Children's Hospital, Dept. of Pediatrics, Medical University of Vienna, Vienna, Austria.
    66Department of Microbiology and Immunology, Medical University of Silesia, Zabrze, Poland.
    67Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.
    68Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France.
    69Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France.
    70Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France.
    71Institute of Pharm. Biology/DCAL, Goethe-University, Frankfurt/Main, Germany.
    Abstract

    Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here, we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements habe been identified so far, of which 94 TPGs are now characterized at the molecular level. Thirty-five out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with ALL and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterisation of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease (MRD) analyses for all patients.Leukemia accepted article preview online, 13 July 2017. doi:10.1038/leu.2017.213.


    Publikations ID: 28701730
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