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

Ute Fischer; 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

doi:10.1038/ng.3362

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

Ute Fischer, 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 CarioHélène 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

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1020-1029
Aantal pagina's	10
Tijdschrift	Nature Genetics
Volume	47
Nummer van het tijdschrift	9
DOI's	https://doi.org/10.1038/ng.3362
Status	Gepubliceerd - 27 aug. 2015
Extern gepubliceerd	Ja

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10.1038/ng.3362

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Fischer, U., Forster, M., Rinaldi, A., Risch, T., Sungalee, S., Warnatz, H. J., Bornhauser, B., Gombert, M., Kratsch, C., Stütz, A. M., Sultan, M., Tchinda, J., Worth, C. L., Amstislavskiy, V., Badarinarayan, N., Baruchel, A., Bartram, T., Basso, G., Canpolat, C., ... Yaspo, M. L. (2015). Genomics and drug profiling of fatal TCF3-HLFâ 'positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nature Genetics, 47(9), 1020-1029. https://doi.org/10.1038/ng.3362

@article{1a3c4431b78c4e76a9f1a30709a1f0ee,

title = "Genomics and drug profiling of fatal TCF3-HLF{\^a} 'positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options",

abstract = "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.",

author = "Ute Fischer and Michael Forster and Anna Rinaldi and Thomas Risch and St{\'e}phanie Sungalee and Warnatz, \{Hans J{\"o}rg\} and Beat Bornhauser and Michael Gombert and Christina Kratsch and St{\"u}tz, \{Adrian M.\} and Marc Sultan and Joelle Tchinda and Worth, \{Catherine L.\} and Vyacheslav Amstislavskiy and Nandini Badarinarayan and Andr{\'e} Baruchel and Thies Bartram and Giuseppe Basso and Cengiz Canpolat and Gunnar Cario and H{\'e}l{\`e}ne Cav{\'e} and Dardane Dakaj and Mauro Delorenzi and Dobay, \{Maria Pamela\} and Cornelia Eckert and Eva Ellinghaus and Sabrina Eugster and Viktoras Frismantas and Sebastian Ginzel and Haas, \{Oskar A.\} and Olaf Heidenreich and Georg Hemmrich-Stanisak and Kebria Hezaveh and H{\"o}ll, \{Jessica I.\} and Sabine Hornhardt and Peter Husemann and Priyadarshini Kachroo and Kratz, \{Christian P.\} and Kronnie, \{Geertruy Te\} and Blerim Marovca and Felix Niggli and McHardy, \{Alice C.\} and Moorman, \{Anthony V.\} and Renate Panzer-Gr{\"u}mayer and Petersen, \{Britt S.\} and Benjamin Raeder and Meryem Ralser and Philip Rosenstiel and Daniel Sch{\"a}fer and Martin Schrappe and Stefan Schreiber and Moritz Sch{\"u}tte and Bj{\"o}rn Stade and Ralf Thiele and Weid, \{Nicolas Von Der\} and Ajay Vora and Marketa Zaliova and Langhui Zhang and Thomas Zichner and Martin Zimmermann and Hans Lehrach and Arndt Borkhardt and Bourquin, \{Jean Pierre\} and Andre Franke and Korbel, \{Jan O.\} and Martin Stanulla and Yaspo, \{Marie Laure\}",

year = "2015",

month = aug,

day = "27",

doi = "10.1038/ng.3362",

language = "English",

volume = "47",

pages = "1020--1029",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Fischer, U, Forster, M, Rinaldi, A, Risch, T, Sungalee, S, Warnatz, HJ, Bornhauser, B, Gombert, M, Kratsch, C, Stütz, AM, Sultan, M, Tchinda, J, Worth, CL, Amstislavskiy, V, Badarinarayan, N, Baruchel, A, Bartram, T, Basso, G, Canpolat, C, Cario, G, Cavé, H, Dakaj, D, Delorenzi, M, Dobay, MP, Eckert, C, Ellinghaus, E, Eugster, S, Frismantas, V, Ginzel, S, Haas, OA, Heidenreich, O, Hemmrich-Stanisak, G, Hezaveh, K, Höll, JI, Hornhardt, S, Husemann, P, Kachroo, P, Kratz, CP, Kronnie, GT, Marovca, B, Niggli, F, McHardy, AC, Moorman, AV, Panzer-Grümayer, R, Petersen, BS, Raeder, B, Ralser, M, Rosenstiel, P, Schäfer, D, Schrappe, M, Schreiber, S, Schütte, M, Stade, B, Thiele, R, Weid, NVD, Vora, A, Zaliova, M, Zhang, L, Zichner, T, Zimmermann, M, Lehrach, H, Borkhardt, A, Bourquin, JP, Franke, A, Korbel, JO, Stanulla, M & Yaspo, ML 2015, 'Genomics and drug profiling of fatal TCF3-HLFâ 'positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options', Nature Genetics, vol. 47, nr. 9, blz. 1020-1029. https://doi.org/10.1038/ng.3362

TY - JOUR

T1 - Genomics and drug profiling of fatal TCF3-HLFâ 'positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options

AU - Fischer, Ute

AU - Forster, Michael

AU - Rinaldi, Anna

AU - Risch, Thomas

AU - Sungalee, Stéphanie

AU - Warnatz, Hans Jörg

AU - Bornhauser, Beat

AU - Gombert, Michael

AU - Kratsch, Christina

AU - Stütz, Adrian M.

AU - Sultan, Marc

AU - Tchinda, Joelle

AU - Worth, Catherine L.

AU - Amstislavskiy, Vyacheslav

AU - Badarinarayan, Nandini

AU - Baruchel, André

AU - Bartram, Thies

AU - Basso, Giuseppe

AU - Canpolat, Cengiz

AU - Cario, Gunnar

AU - Cavé, Hélène

AU - Dakaj, Dardane

AU - Delorenzi, Mauro

AU - Dobay, Maria Pamela

AU - Eckert, Cornelia

AU - Ellinghaus, Eva

AU - Eugster, Sabrina

AU - Frismantas, Viktoras

AU - Ginzel, Sebastian

AU - Haas, Oskar A.

AU - Heidenreich, Olaf

AU - Hemmrich-Stanisak, Georg

AU - Hezaveh, Kebria

AU - Höll, Jessica I.

AU - Hornhardt, Sabine

AU - Husemann, Peter

AU - Kachroo, Priyadarshini

AU - Kratz, Christian P.

AU - Kronnie, Geertruy Te

AU - Marovca, Blerim

AU - Niggli, Felix

AU - McHardy, Alice C.

AU - Moorman, Anthony V.

AU - Panzer-Grümayer, Renate

AU - Petersen, Britt S.

AU - Raeder, Benjamin

AU - Ralser, Meryem

AU - Rosenstiel, Philip

AU - Schäfer, Daniel

AU - Schrappe, Martin

AU - Schreiber, Stefan

AU - Schütte, Moritz

AU - Stade, Björn

AU - Thiele, Ralf

AU - Weid, Nicolas Von Der

AU - Vora, Ajay

AU - Zaliova, Marketa

AU - Zhang, Langhui

AU - Zichner, Thomas

AU - Zimmermann, Martin

AU - Lehrach, Hans

AU - Borkhardt, Arndt

AU - Bourquin, Jean Pierre

AU - Franke, Andre

AU - Korbel, Jan O.

AU - Stanulla, Martin

AU - Yaspo, Marie Laure

PY - 2015/8/27

Y1 - 2015/8/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84940575993

U2 - 10.1038/ng.3362

DO - 10.1038/ng.3362

M3 - Article

C2 - 26214592

AN - SCOPUS:84940575993

SN - 1061-4036

VL - 47

SP - 1020

EP - 1029

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

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