Mutational spectrum of adult T-ALL.

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

doi:10.18632/oncotarget.2218

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.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) in adults represents a disease with an unfavorable outcome[1]
After exclusion of polymorphisms annotated in dbSNP135, 473 single nucleotide variations (SNVs) and short indels were identified with a minimum call of 20 reads, 313 of those resulted in changes in the coding sequence of the target region
Risk stratification and subsequent therapy intensification have led to an improved outcome in adult T-ALL, the cure rate of approximately 50% remains unsatisfactory

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) in adults represents a disease with an unfavorable outcome[1]. While the cure rate in pediatric T-ALL patients exceeds 70%, a similar rate in adults is only observed for patients in the favorable risk group of thymic T-ALL as defined by the expression of CD1a[2,3]. Allogeneic stem cell transplantation (alloSCT) in first complete remission has led to an improved outcome e.g. in the context of the German Multicenter Acute Lymphoblastic Leukemia (GMALL) trials, further therapeutic improvements are urgently warranted, in particular for high risk patients. In B-cell precursor (BCP-) ALL molecularly directed therapies like Rituxumab[4], the bi-specific antibody Blinatumomab[5], or tyrosine kinase inhibitors in Ph+-ALL[6] are well established. In order to identify targets for specific treatment strategies, a better understanding of the molecular background of T-ALL is necessary[8]

Methods

Results

Conclusion