Mutational spectrum of adult T-ALL

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.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…In recent years, next-generation sequencing techniques, including whole-genome sequencing, whole-exome sequencing (WES), and RNA sequencing (RNA-seq), have extended the list of genetic abnormalities in T-ALL to epigenetic factors and translation/RNA stability pathways (16)(17)(18)(19)(20)(21). Of note, a subgroup of T-ALL with a characteristic immunophenotype (CD3…”

Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

“…It has been reported that DNM2 gene mutation is an important factor for patients with autosomal dominant centronuclear myopathy (20) and Alzheimer's disease (21,22). Recurrent DNM2 mutations have also been identified in patients with ETP-ALL by whole-exome sequencing (6,10,23). These mutations include: E78fs in the Ras-like GTPase domain; L3354P, R364C, K382E, T404N and E468 * in the dynamin MD domain; S528fs, E544fs and K557_K558>K in the PH domain; S698L in the GTPase effector domain; and K770 * , P791T, L789fs and I805fs in the C-terminus.…”

“…Previously, T-ALL was classified into five subgroups (pro-T, pre-T, cortical, mature T-ALL and ETP) based on the results of fluorescent in situ hybridization (FISH), molecular biology and gene expression profiling (4). With exome-sequencing and whole genome sequencing, genetic mutations on genes including NOTCH1, F-box and WD repeat domain containing 7 (FBXW7), Ras, PHD finger protein 6 (PHF6) and Janus kinase 1 (JAK1) have been found to be high-risk markers in patients with T-ALL (3,5,6).…”

“…Inhibition of DNM2 induced cell death in 11 cancer cell lines (9). Previously, DNM2 genetic mutations were identified in a subtype of T-ALL, termed early T-cell precursor (ETP) ALL, which accounts for up to 15% of T-ALL and is associated with a high risk of treatment failure (6,10). However, to the best of our knowledge, no studies have investigated DNM2 genetic mutations in adult ALL.…”

Epigenetics of hematopoiesis and hematological malignancies

“…The MLL3 mutation or its deletion is found in hematological malignancies, including 15% of DLBCL, MDS, and AML (Mrozek 2008;Pasqualucci et al 2011;Zhang et al 2013). MLL4 (GeneID 8085) mutations are prevalent in NHL Pasqualucci et al 2011;Lohr et al 2012;Green et al 2015), ALL (Mar et al 2012;Lindqvist et al 2015;Neumann et al 2015), and AML (Kandoth et al 2013). Most of the MLL3 and MLL4/COMPASS mutations are heterozygous nonsense, frameshift, and internal insertions/deletions (indels), resulting in protein truncations-which is suggestive of a haploinsufficient tumor suppressor function of MLL3 and MLL4 (GeneID 8085)-in cancer pathogenesis.…”