T-Cell Acute Lymphoblastic Leukemia Can be Subdivided into Six Genetically Distinct Subtypes with Prognostic Impact By Combination of Whole Genome and Whole Transcriptome Data

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a rare aggressive neoplasm accounting for ∼20% of all ALL cases. It is more common in adults than in children, although the incidence decreases with older age. Subclassification of T-ALL cases according to WHO is so far solely based on the immunophenotype. Although a number of common molecular aberrations have been described in T-ALL, a molecular classification of T-ALLs so far is missing. Aim: (1) Molecular subclassification of T-ALL cases based on whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) data. (2) Analysis of correlations between aberrations, subgroups and other parameters. Methods: WGS and WTS were performed in 114 patients. For WGS, 151bp paired-end reads were generated on NovaSeq 6000 and HiSeqX machines (Illumina, San Diego, CA). For WTS, 101 bp paired-end reads were produced on a NovaSeq 6000 system with a yield between 35 and 125 million paired reads per sample. SPSS (version 19.0.0, IBM Corporation, Armonk, NY) was used for statistical analysis. Results: The cohort comprised 114 T-ALL cases (29% female, 71% male) with a median age of 37 years (range 1 - 91 years). Based on mutations (mut), translocations and gene expression, the cases were subdivided into six different groups: group 1 (n=20) was defined by overexpression (oex) of TLX1 (by t(10;14)(q24;q11)/TRAD-TLX1, n=17; t(7;10)(q34;q24)/TRB-TLX1, n=2; inv(10)(q23q24), n=1) and was correlated to a high frequency of mut in NOTCH1 (19/20, 95%, p=0.011 compared to the other T-ALL cases), PHF6 (11/20, 55%, p=0.04) and BCL11B (5/20, 25%, p=0.004). Group 2 (n=9) showed TLX3 oex by t(5;14)(q35;q32)/BCL11B-TLX3 (n=8) or t(5;8)(q35;q24) (n=1). Mut in WT1 (5/9 = 56%, p Conclusions: (1) The combination of WGS and WTS successfully subclassified T-ALL cases on a molecular level into six different groups, by oex of TLX1, TLX3, HOXA or TAL1 and presence/absence of NOTCH1 mut. (2) We identified a novel so far unknown type of NOTCH1 aberrations, termed NOTCH1-ITD. (3) Molecular sub-classification of T-ALL cases also impacts on prognosis (TLX1 and HOXA group, longer OS; NOTCH1+ and TAL1 group, shorter OS). Download : Download high-res image (930KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.