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 have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 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 acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization 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 analyses for all patients.

Belarusian Research Center for Pediatric Oncology Hematology and Immunology Minsk Republic of Belarus

Biological Hematology AP HP A Trousseau Pierre et Marie Curie University Paris France

Bristol Genetics Laboratory Pathology Sciences Southmead Hospital North Bristol NHS Trust Bristol UK

Center for Diagnostic University Medical Center Hamburg Eppendorf Hamburg Germany

Centro Ricerca Tettamanti Clinica Pediatrica Univ Milano Bicocca Monza Italy

Charité Department of Hematology Oncology and Tumorimmunology Berlin Germany

Children's Cancer Institute Australia Uinversity of NSW Sydney Sydney New South Wales Australia

Children's Cancer Research Institute and St Anna Children's Hospital Department of Pediatrics Medical University of Vienna Vienna Austria

CHU Purpan Laboratoire d'Hématologie Toulouse France

CIBER de Cancer ISCIII Madrid Spain

CLIP Department of Paediatric Haematology Oncology Charles University Prague 2nd Faculty of Medicine Prague Czech Republic

Cytogenetics Department Bone Marrow Transplantation Unit National Cancer Institute Rio de Janeiro Brazil

Department of Clinical Chemistry and TYKSLAB University of Turku and Turku University Central Hospital Turku Finland

Department of Clinical Immunology University Hospital Rigshospitalet Copenhagen Denmark

Department of Experimental Pathology and Cytology Institute of Pathology Giessen Germany

Department of Genetics AP HP Robert Debré Paris Diderot University Paris France

Department of Human Genetics Hannover Medical School Hanover Germany

Department of Laboratory Medicine Inje University College of Medicine Busan Korea

Department of Laboratory Medicine School of Medicine Kyung Hee University Seoul Korea

Department of Microbiology and Immunology Medical University of Silesia Zabrze Poland

Department of Oncology University Children's Hospital Zurich Zurich Switzerland

Department of Pediatric Hematology and Oncology Medical University of Silesia Zabrze Poland

Department of Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Department of Pediatrics Jena University Hospital Jena Germany

Department of Pediatrics MHH Hanover Germany

Department of Pediatrics Portuguese Institute of Oncology of Lisbon Lisbon Portugal

Department of Pediatrics University Medical Centre Schleswig Holstein Kiel Germany

Dmitry Rogachev National Scientific and Practical Center of Pediatric Hematology Oncology and Immunology Moscow

Erasmus MC Department of Immunology Rotterdam The Netherlands

Hemato Oncology Laboratory UIPM Portuguese Institute of Oncology of Lisbon Lisbon Portugal

Hématologie Biologique CHU de Brest and INSERM U1078 Université de Bretagne Occidentale Brest France

Hospital Nacional de Pediatría Prof Dr J P Garrahan Servcio de Hemato Oncología Buenos Aires Argentina

Institucio Catalana de Recerca i Estudis Avançats Barcelona Spain

Institute of Pharmaceutical Biology Diagnostic Center of Acute Leukemia Goethe University Frankfurt Main Germany

Josep Carreras Leukemia Research Institute Department of Biomedicine School of Medicine University of Barcelona Barcelona Spain

Laboratoire d'hématologie AP HP Saint Louis Paris Diderot University Paris France

Laboratory of Clinical Genetics Fimlab Laboratories Tampere Finland

Laboratory of Hematology Biology and Pathology Center CHRU of Lille; INSERM UMR S 1172 Cancer Research Institute of Lille Lille France

Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne UK

Pediatric Hematology Oncology Program Research Center Instituto Nacional de Cancer Rio de Janeiro Rio de Janeiro Brazil

Regional Children Hospital 1 Research Institute of Medical Cell Technologies Pediatric Oncology and Hematology Center Ural Federal University Ekaterinburg Russia

Sackler Medical School Tel Aviv University Tel Aviv Israel

The Chaim Sheba Medical Center Department of Pediatric Hemato Oncology and the Cancer Research Center Tel Aviv Israel

The Great North Children's Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

The University of Queensland Diamantina Institute The University of Queensland Brisbane Queensland Australia

Université de Bretagne Occidentale Faculté de Médecine et des Sciences de la Santé Laboratoire d'Histologie Embryologie et Cytogénétique and INSERM U1078 Brest France

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