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6. Detection of MLL genomic breakpoints in infant acute leukemia

Author

Tsaur, G. A., Meyer, C., Popov, A. M., Piekhanova, O. M., Kustanovich, A. M., Volochnik, E. V., Riger, T. O., Demina, A. S., A.E. Druy, Fieischman, E. W., Sokova, O. I., Olshariskaya, Yu V., Streneva, O. V., Shorikov, E. V., Saveliev, L. I., Marschalek, R., Kutsev, S. I., Tsvirenko, S. V., and Fechina, L. G.

10. The MLL recombinome of acute leukemias in 2017

Author

Elena Zerkalenkova, A Bidet, Anatoly Kustanovich, C Barbieri Blunck, Hans O. Madsen, Jeremy Hancock, Sabine Strehl, Hélène Cavé, Beat W. Schäfer, Aurélie Caye, Jana Lentes, L Corral Abascal, Giovanni Cazzaniga, B Almeida Lopes, M. De Braekeleer, Eric Lippert, Aline Renneville, Grigory Tsaur, Julia Alten, Oskar A. Haas, Lukasz Sedek, Eric Delabesse, Martin Stanulla, Maria Luiza Macedo Silva, Emmanuelle Clappier, Anja Möricke, Christian Meyer, Mariana Emerenciano, Martin Schrappe, Hélène Lapillonne, Rosemary Sutton, Thomas Burmeister, Rolf Marschalek, Michael Dworzak, T Lund-Aho, V H J van der Velden, Clara Bueno, Paola Ballerini, Jan Trka, Maria S. Pombo-de-Oliveira, Yulia Olshanskaya, Daniela Gröger, Shai Izraeli, Olga Aleinikova, Gudrun Göhring, Vesa Juvonen, Andishe Attarbaschi, Nicola C. Venn, S Kubetzko, J M Cayuela, Andrew S. Moore, T S Park, Paula Gameiro, S H Oh, Christian M. Zwaan, Renate Panzer-Grümayer, L Suarez, X Duarte, Josef Vormoor, Olaf Heidenreich, P Archer, Pablo Menendez, Bernd Gruhn, Jan Zuna, Cristina N. Alonso, M M van den Heuvel-Eibrink, Andrea Teigler-Schlegel, L. Trakhtenbrot, U zur Stadt, L Fechina, Tomasz Szczepański, Immunology, Pediatrics, Meyer, C, Burmeister, T, Gröger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, N, Emerenciano, M, Pombo-De-Oliveira, M, Barbieri Blunck, C, Almeida Lopes, B, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Corral Abascal, L, Van Der Velden, V, Delabesse, E, Park, T, Oh, S, Silva, M, Lund-Aho, T, Juvonen, V, Moore, A, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, Zur Stadt, U, Lentes, J, Göhring, G, Kustanovich, A, Aleinikova, O, Schäfer, B, Kubetzko, S, Madsen, H, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, J, Clappier, E, Alonso, C, Zwaan, C, Van Den Heuvel-Eibrink, M, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Möricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, O, Panzer-Grümayer, R, Sedék, L, Szczepa, T, Caye, A, Suarez, L, Cavé, H, and Marschalek, R

Subjects
0301 basic medicine, Adult, Male, Cancer Research, MED/03 - GENETICA MEDICA, Oncogene Proteins, Fusion, Chromosome Aberration, Translocation, Genetic, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Child, neoplasms, Genetics, Chromosome Aberrations, Gene Rearrangement, Acute leukemia, biology, Breakpoint, Infant, Chromosome Breakage, Hematology, Gene rearrangement, Histone-Lysine N-Methyltransferase, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, ta3122, Minimal residual disease, 3. Good health, Leukemia, Leukemia, Myeloid, Acute, 030104 developmental biology, KMT2A, Oncology, 030220 oncology & carcinogenesis, biology.protein, Myeloid-Lymphoid Leukemia Protein, Original Article, Female, Chromosome breakage, Human
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 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.

Published
2018
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11. The MLL recombinome of acute leukemias in 2013

Author

E. Launay, Vesa Juvonen, Julia Hofmann, Emmanuelle Clappier, T S Park, M.M. van den Heuvel-Eibrink, Anja Möricke, S. Kubetzko, V H J van der Velden, Aline Renneville, Eric Delabesse, William W.L. Choi, Paula Gameiro, Jean Michel Cayuela, L Fechina, Jong Rak Choi, Cristina N. Alonso, Theodor Dingermann, Clara Bueno, U. Zur Stadt, P. Archer, Martin Stanulla, Mary Callanan, Manuel R. Teixeira, Catherine Henry, Marie Jarošová, Nuno Cerveira, Daniela Gröger, M. De Braekeleer, Thomas Burmeister, H. Lapillone, Rosemary Sutton, G te Kronnie, K. Mass-Malo, J J M van Dongen, Jeremy Hancock, Cornelia Eckert, E De Braekeleer, Olga V. Aleinikova, Mara Silva, Sylvie Tondeur, Tomasz Szczepański, Renata Binato, Christian M. Zwaan, Martin Schrappe, Claus Meyer, Eric Lippert, P. M. Kakadiya, Paola Ballerini, Martina Ahlmann, Renate Panzer-Grümayer, Hélène Cavé, Michael Dworzak, Lukasz Sedek, S. Wehner, Dongsoon Lee, Josef Vormoor, Olaf Heidenreich, A. Kolenova, Shai Izraeli, Pascaline Talmant, Elizabeth Macintyre, Charles Herbaux, AM Kustanovich, Stefan K. Bohlander, Jan Trka, Grigory Tsaur, N. C. Venn, Luba Trakhtenbrot, Thomas Klingebiel, Pablo Menendez, T Lund-Aho, Mariana Emerenciano, Pascale Cornillet-Lefebvre, Juergen Krauter, Sabine Strehl, Beat W. Schäfer, M. Pombo De Oliveira, Marian H. Harris, H. O. Madsen, Patrick Villarese, Eva A. Coenen, Jan Zuna, L Lo Nigro, Giovanni Cazzaniga, S H Oh, Rolf Marschalek, Immunology, Pediatrics, Meyer, C, Hofmann, J, Burmeister, T, Gröger, D, Park, T, Emerenciano, M, Pombo de Oliveira, M, Renneville, A, Villarese, P, Macintyre, E, Cavé, H, Clappier, E, Mass-Malo, K, Zuna, J, Trka, J, De Braekeleer, E, De Braekeleer, M, Oh, S, Tsaur, G, Fechina, L, van der Velden, V, van Dongen, J, Delabesse, E, Binato, R, Silva, M, Kustanovich, A, Aleinikova, O, Harris, M, Lund-Aho, T, Juvonen, V, Heidenreich, O, Vormoor, J, Choi, W, Jarosova, M, Kolenova, A, Bueno, C, Menendez, P, Wehner, S, Eckert, C, Talmant, P, Tondeur, S, Lippert, E, Launay, E, Henry, C, Ballerini, P, Lapillone, H, Callanan, M, Cayuela, J, Herbaux, C, Cazzaniga, G, Kakadiya, P, Bohlander, S, Ahlmann, M, Choi, J, Gameiro, P, Lee, D, Krauter, J, Cornillet-Lefebvre, P, Te Kronnie, G, Schäfer, B, Kubetzko, S, Alonso, C, zur Stadt, U, Sutton, R, Venn, N, Izraeli, S, Trakhtenbrot, L, Madsen, H, Archer, P, Hancock, J, Cerveira, N, Teixeira, M, Lo Nigro, L, Möricke, A, Stanulla, M, Schrappe, M, Sedék, L, Szczepański, T, Zwaan, C, Coenen, E, van den Heuvel-Eibrink, M, Strehl, S, Dworzak, M, Panzer-Grümayer, R, Dingermann, T, Klingebiel, T, and Marschalek, R

Subjects
MLL, Male, Cancer Research, Oncogene Proteins, Fusion, Polymerase Chain Reaction, Translocation, Genetic, chromosomal translocations, Mice, 0302 clinical medicine, AML, hemic and lymphatic diseases, Age Factor, acute leukemia, Child, Genetics, Aged, 80 and over, Gene Rearrangement, 0303 health sciences, Acute leukemia, Leukemia, biology, Age Factors, Chromosome Breakage, Hematology, Middle Aged, Prognosis, 3. Good health, translocation partner genes, KMT2A, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Acute Disease, Myeloid-Lymphoid Leukemia Protein, Original Article, Female, Chromosome breakage, Human, Adult, Adolescent, Prognosi, Chromosomal rearrangement, ta3111, 03 medical and health sciences, Young Adult, medicine, Animals, Humans, neoplasms, 030304 developmental biology, Aged, Animal, Breakpoint, Infant, Newborn, Infant, Gene rearrangement, Histone-Lysine N-Methyltransferase, medicine.disease, ta3122, biology.protein, ALL
Abstract

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Published
2013

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