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

dc.contributor.authorFischer, Ute
dc.contributor.authorForster, Michael
dc.contributor.authorRinaldi, Anna
dc.contributor.authorRisch, Thomas
dc.contributor.authorSungalee, Stephanie
dc.contributor.authorWarnatz, Hans-Joerg
dc.contributor.authorBornhauser, Beat
dc.contributor.authorGombert, Michael
dc.contributor.authorKratsch, Christina
dc.contributor.authorStuetz, Adrian M.
dc.contributor.authorSultan, Marc
dc.contributor.authorTchinda, Joelle
dc.contributor.authorWorth, Catherine L.
dc.contributor.authorAmstislavskiy, Vyacheslav
dc.contributor.authorBadarinarayan, Nandini
dc.contributor.authorBaruchel, Andre
dc.contributor.authorBartram, Thies
dc.contributor.authorBasso, Giuseppe
dc.contributor.authorCanpolat, Cengiz
dc.contributor.authorCario, Gunnar
dc.contributor.authorCave, Helene
dc.contributor.authorDakaj, Dardane
dc.contributor.authorDelorenzi, Mauro
dc.contributor.authorDobay, Maria Pamela
dc.contributor.authorEckert, Cornelia
dc.contributor.authorEllinghaus, Eva
dc.contributor.authorEugster, Sabrina
dc.contributor.authorFrismantas, Viktoras
dc.contributor.authorGinzel, Sebastian
dc.contributor.authorHaas, Oskar A.
dc.contributor.authorHeidenreich, Olaf
dc.contributor.authorHemmrich-Stanisak, Georg
dc.contributor.authorHezaveh, Kebria
dc.contributor.authorHoell, Jessica I.
dc.contributor.authorHornhardt, Sabine
dc.contributor.authorHusemann, Peter
dc.contributor.authorKachroo, Priyadarshini
dc.contributor.authorKratz, Christian P.
dc.contributor.authorte Kronnie, Geertruy
dc.contributor.authorMarovca, Blerim
dc.contributor.authorNiggli, Felix
dc.contributor.authorMcHardy, Alice C.
dc.contributor.authorMoorman, Anthony V.
dc.contributor.authorPanzer-Gruemayer, Renate
dc.contributor.authorPetersen, Britt S.
dc.contributor.authorRaeder, Benjamin
dc.contributor.authorRalser, Meryem
dc.contributor.authorRosenstiel, Philip
dc.contributor.authorSchaefer, Daniel
dc.contributor.authorSchrappe, Martin
dc.contributor.authorSchreiber, Stefan
dc.contributor.authorSchuette, Moritz
dc.contributor.authorStade, Bjoern
dc.contributor.authorThiele, Ralf
dc.contributor.authorvon der Weid, Nicolas
dc.contributor.authorVora, Ajay
dc.contributor.authorZaliova, Marketa
dc.contributor.authorZhang, Langhui
dc.contributor.authorZichner, Thomas
dc.contributor.authorZimmermann, Martin
dc.contributor.authorLehrach, Hans
dc.contributor.authorBorkhardt, Arndt
dc.contributor.authorBourquin, Jean-Pierre
dc.contributor.authorFranke, Andre
dc.contributor.authorKorbel, Jan O.
dc.contributor.authorStanulla, Martin
dc.contributor.authorYaspo, Marie-Laure
dc.date.accessioned2023-02-21T12:42:22Z
dc.date.available2023-02-21T12:42:22Z
dc.date.issued2015-01-01
dc.description.abstractTCF3-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.
dc.description.issue9
dc.description.issueSEP
dc.description.pages1020+
dc.description.volume47
dc.identifier.doi10.1038/ng.3362
dc.identifier.urihttps://hdl.handle.net/11443/2808
dc.identifier.urihttp://dx.doi.org/10.1038/ng.3362
dc.identifier.wosWOS:000360394100012
dc.publisherNATURE PUBLISHING GROUP
dc.relation.ispartofNATURE GENETICS
dc.titleGenomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
dc.typeArticle

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