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Neumann, M.* ; Vosberg, S. ; Schlee, C.* ; Heesch, S.* ; Schwartz, S.* ; Gökbuget, N.* ; Hoelzer, D.* ; Graf, A.* ; Krebs, S.* ; Bartram, I.* ; Blum, H.* ; Brüggemann, M.* ; Hecht, J.* ; Bohlander, S.K. ; Greif, P.A. ; Baldus, C.D.*

Mutational spectrum of adult T-ALL.

Oncotarget 6, 2754-2766 (2014)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Lymphoblastic Leukemia ; Gene Panel ; Pathways ; T-all Next Generation Sequencing ; Targeted Therapy; Acute Lymphoblastic-leukemia; Acute Myeloid-leukemia; Prognostic Implications; Activating Mutations; Tumor-suppressor; Fbxw7 Mutations; Gene-expression; Cell Leukemia; B-lineage; Notch1
Language english
Publication Year 2014
HGF-reported in Year 2015
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Journal OncoTarget
Quellenangaben Volume: 6, Issue: 5, Pages: 2754-2766 Article Number: , Supplement: ,
Publisher Impact Journals LLC
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-521000-001
PubMed ID 25595890
WOS ID WOS:000352694400016
Scopus ID 84923293351
DOI 10.18632/oncotarget.2218
Erfassungsdatum 2015-01-19
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