Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options

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TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease. … celý popis

Podrobná bibliografie

Hlavní autor:

Ute Fischer

Další autoři:

Michael Forster, Anna Rinaldi, Thomas Risch, Stéphanie Sungalee, Hans-Jörg Warnatz, Beat Bornhauser, Michael Gombert, Christina Kratsch, Adrian M Stütz, Marc Sultan, Joelle Tchinda, Catherine L Worth, Vyacheslav Amstislavskiy, Nandini Badarinarayan, André Baruchel, Thies Bartram, Giuseppe Basso, Cengiz Canpolat, Gunnar Cario, Hélène Cavé, Dardane Dakaj, Mauro Delorenzi, Maria Pamela Dobay, Cornelia Eckert, Eva Ellinghaus, Sabrina Eugster, Viktoras Frismantas, Sebastian Ginzel, Oskar A Haas, Olaf Heidenreich, Georg Hemmrich-Stanisak, Kebria Hezaveh, Jessica I Höll, Sabine Hornhardt, Peter Husemann, Priyadarshini Kachroo, Christian P Kratz, Geertruy Te Kronnie, Blerim Marovca, Felix Niggli, Alice C McHardy, Anthony V Moorman, Renate Panzer-Grümayer, Britt S Petersen, Benjamin Raeder, Meryem Ralser, Philip Rosenstiel, Daniel Schäfer, Martin Schrappe, Stefan Schreiber, Moritz Schütte, Björn Stade, Ralf Thiele, Nicolas von der Weid, Ajay Vora, Marketa Zaliova, Langhui Zhang, Thomas Zichner, Martin Zimmermann, Hans Lehrach, Arndt Borkhardt, Jean-Pierre Bourquin, Andre Franke, Jan O Korbel, Martin Stanulla, Marie-Laure Yaspo

Typ dokumentu:

Články

Publikováno v:

Nature genetics. -- ISSN 1546-1718. -- Roč. 47, č. 9 (2015), s. 1020-9

Témata:

zvířata

antitumorózní látky > farmakologie > terapeutické užití

aktivátorový protein specifický pro B-buňky > genetika

kokultivační techniky

kohortové studie

mutační analýza DNA

chemorezistence

ženské pohlaví

exprese genu

genetické asociační studie

genomika

lidé

náhradní lehké řetězce imunoglobulinů > genetika

inhibiční koncentrace 50

Kaplanův-Meierův odhad

mužské pohlaví

myši inbrední NOD

myši SCID

mutace

fúzní onkogenní proteiny > genetika > metabolismus

akutní lymfatická leukemie > farmakoterapie > genetika > mortalita

sekvenční delece

xenogenní modely - testy antitumorózní aktivity

časopisecké články

práce podpořená grantem