UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment
Creators: name: Bastian, Lorenz
name: Hartmann, Alina M.
name: Beder, Thomas
name: Hänzelmann, Sonja
name: Kässens, Jan
name: Bultmann, Miriam
name: Hoeppner, Marc P.
name: Franzenburg, Sören
name: Wittig, Michael
name: Franke, Andre
name: Nagel, Inga
name: Spielmann, Malte
name: Reimer, Niklas
name: Busch, Hauke
name: Schwartz, Stefan
name: Steffen, Björn
name: Viardot, Andreas
name: Döhner, Konstanze
name: Kondakci, Mustafa
name: Wulf, Gerald
name: Wendelin, Knut
name: Renzelmann, Andrea
name: Kiani, Alexander
name: Trautmann, Heiko
name: Neumann, Martin
name: Gökbuget, Nicola
name: Brüggemann, Monika
name: Baldus, Claudia D.
Publisher: name: Universität Ulm
Year: 2022
Subjects: subject: Cancer genomics
subject: Oncogenesis
subject: DDC 610 / Medicine &amp; health

description: We performed transcriptome sequencing (RNA-Seq) on n = 568 adult BCP-ALL patients prospectively treated according to pediatric-based protocols of the German Multicenter Acute Lymphoblastic Leukemia (GMALL) study group including risk stratification based on minimal residual disease (MRD) and treatment intensification for high-risk patients. To define molecular subtypes, we used our previous integrative analyses [1] to train a machine learning classifier to predict subtype allocation from gene expression profiles of subsequently sequenced samples. Feature selection (LASSO) was used to identify the most informative genes. Underlying genomic aberrations were analyzed (whole-genome sequencing (WGS), whole-exome sequencing (WES); SNP-arrays) to confirm subtype allocation in selected cases. With this approach, we were able to allocate n = 535/568 (94%) samples to 15 previously established [1] molecular subtypes (Fig. 1A–D), with confirmation of corresponding genomic alterations in 91% of analyzed cases (Fig. 1D). Unsupervised gene expression analysis of previously unassigned samples revealed a distinct patient subset (n = 12; Supplementary Fig. S1A) defined by a novel in-frame gene fusion of upstream binding transcription factor (UBTF) and ataxin-7-like protein 3 (ATXN7L3) occurring exclusively in this patient cluster (n = 12/12 vs. n = 0/556 in remaining cohort, p &lt; 1E−10; Fig. 1D). Comparison of gene expression profiles revealed that UBTF::ATXN7L3 rearranged cases in our cohort match to a recently described BCP-ALL subtype, which so far was identified by increased expression of the homeobox transcription factor CDX2 (‘CDX2 high’ ALL) [2] (Supplementary Fig. S1B). UBTF::ATXN7L3 represents an 11.3 kbp in-frame read-through between UBTF exon 17/21 and a 5′ UTR splice site of ATXN7L3, with the same sanger sequencing confirmed break point in all samples (Fig. 2A, Supplementary Methods). WGS of 3 samples revealed a 10.08 kb genomic deletion involving UBTF 3′ exons (18-21) and most of the intergenic region between UBTF and ATXN7L3 as underlying mechanism (Fig. 2A, Supplementary Fig. S2). Break-point-specific PCR and Sanger sequencing confirmed presence of the deletion in n = 11/11 UBTF::ATXN7L3 patients with available material (Supplementary Fig. S3). The same ATXN7L3 transcript breakpoint has previously been identified in a patient with diffuse large B cell lymphoma (GPATCH8::ATXN7L3) [3], suggesting a shared driver function in different B-lymphoid malignancies. Both fusion partners were highly expressed across the entire cohort without significant differences in the novel subtype (Supplementary Fig. S4), suggesting either gain-of-function or a dominant-negative effect of the gene fusion.