Oncotarget

Research Papers:

Mutational spectrum of adult T-ALL

Martin Neumann, Sebastian Vosberg, Cornelia Schlee, Sandra Heesch, Stefan Schwartz, Nicola Gökbuget, Dieter Hoelzer, Alexander Graf, Stefan Krebs, Isabelle Bartram, Helmut Blum, Monika Brüggemann, Jochen Hecht, Stefan K. Bohlander, Philipp A. Greif, Claudia D. Baldus _

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Oncotarget. 2015; 6:2754-2766. https://doi.org/10.18632/oncotarget.2218

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Abstract

Martin Neumann1, Sebastian Vosberg2,3, Cornelia Schlee1, Sandra Heesch1, Stefan Schwartz1, Nicola Gökbuget4, Dieter Hoelzer4, Alexander Graf5, Stefan Krebs5, Isabelle Bartram1, Helmut Blum5, Monika Brüggemann6, Jochen Hecht7, Stefan K. Bohlander2,8, Philipp A. Greif2,3,9,10,* and Claudia D. Baldus1,9,*

1 Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany

2 Clinical Cooperative Group ‘Leukemia’, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

3 Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany

4 Goethe University Hospital, Department of Medicine II, Hematology/Oncology, Frankfurt/M., Germany

5 Laboratory for Functional Genome Analysis, Gene-Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany

6 University Hospital Kiel, Department of Hematology, University Hospital Schleswig-Holstein, Campus Kiel, Germany

7 Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany

8 Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand

9 German Cancer Consortium (DKTK), Heidelberg, Germany

10 German Cancer Research Centre (DKFZ), Heidelberg, Germany

* These authors contributed equally to this work

Correspondence:

Claudia D. Baldus, email:

Keywords: Acute lymphoblastic leukemia, targeted therapy, T-ALL next generation sequencing, pathways, gene panel

Received: May 20, 2014 Accepted: July 13, 2014 Published: July 15, 2014

Abstract

Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.


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