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. 2022 Jun;36(6):1676-1680.
doi: 10.1038/s41375-022-01557-6. Epub 2022 Apr 9.

UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment

Lorenz Bastian  1   2   3 , Alina M Hartmann  1   2   3 , Thomas Beder  1   2   3 , Sonja Hänzelmann  1   2   3 , Jan Kässens  1   2 , Miriam Bultmann  1   2 , Marc P Hoeppner  3   4 , Sören Franzenburg  4 , Michael Wittig  4 , Andre Franke  4 , Inga Nagel  5 , Malte Spielmann  5   6 , Niklas Reimer  2   7   8 , Hauke Busch  2   7   8 , Stefan Schwartz  9 , Björn Steffen  10 , Andreas Viardot  11 , Konstanze Döhner  11 , Mustafa Kondakci  12 , Gerald Wulf  13 , Knut Wendelin  14 , Andrea Renzelmann  15 , Alexander Kiani  16   17 , Heiko Trautmann  1   2 , Martin Neumann  1   2   3 , Nicola Gökbuget  10 , Monika Brüggemann  1   2   3 , Claudia D Baldus  18   19   20
Affiliations

UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment

Lorenz Bastian et al. Leukemia. 2022 Jun.
No abstract available

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Conflict of interest statement

MBr received personal fees from Incyte (advisory board) and Roche Pharma AG, financial support for reference diagnostics from Affimed and Regeneron, grants and personal fees from Amgen (advisory board, speakers bureau, travel support), and personal fees from Janssen (speakers bureau), all outside the submitted work. The remaining authors declare no competing financial interests. None of the remaining authors has a relevant conflict of interest.

Figures

Fig. 1
Fig. 1. UBTF::ATXN7L3 gene fusion defines a BCP-ALL molecular subtype.
Bone marrow or peripheral blood samples of n = 568 adult patients at first diagnosis of BCP-ALL with at least 20% blast infiltration were analyzed by transcriptome sequencing. Gene expression profiles of previously established definitions [1] were used to train a machine learning algorithm (Extreme Gradient Boosting) with feature selection (LASSO) to allocate samples to 15 established and 2 novel BCP-ALL subtypes. A Uniform manifold approximation and projection (UMAP) plot depicts distribution of molecular ALL subtypes based on expression of the top informative genes for subgroup allocation. B Unsupervised clustering of gene expression specific for the novel UBTF::ATXN7L3 subgroup. Subtype-specific gene sets were identified by multi-comparison ANOVA using the variance stabilizing transformation for normalizing expression values. Genes had to be differentially expressed to at least 11 other subtypes with an FDR-corrected p value ≤ 0.01 (Supplementary Table S1,2). C Expression of selected UBTF::ATXN7L3-specific oncogenes is shown in comparison to other molecular subtypes with at least three samples. The complete list of Cosmic cancer gene census genes differentially expressed by multi-comparison ANOVA in UBTF::ATXN7L3 ALL is shown in Supplementary Table S2. Expression of cancer-associated genes upregulated in UBTF::ATXN7L3 in comparison to other molecular subtypes is shown in Supplementary Figure S6. D Subtype-specific driver fusions and the novel candidate driver gene fusion UBTF::ATXN7L3 were called from RNA-Seq data (FusionCatcher) [15] Virtual karyotypes were obtained from whole-exome sequencing or SNP-Arrays (Illumina Infinium Global Screen array v3.0) to support classification of aneuploid subtypes. Subtype-specific hotspot driver mutations (eg. PAX5) were called from RNA-Seq data. Heatmap depicts probabilities for allocation of samples to the molecular subtypes (class probabilities) obtained by the gene expression-based machine learning classifier together with corresponding genomic driver events. * indicates one UBTF::ATXN7L3 sample with 20% blast content, where the driver gene fusion was not called by FusionCatcher but was confirmed by break-point specific PCR and sanger sequencing (Supplementary Fig. S7B).
Fig. 2
Fig. 2. UBTF::ATXN7L3 ALL patients experience poor responses to conventional chemotherapy and successful salvage by MRD-stratified treatment intensification including immunotherapies.
A The structure of UBTF::ATXN7L3 fusion is shown. Above: whole-genome sequencing read alignment from one representative sample (I29815) with reads depicted as pairs and red highlighting insert lengths above the 99.5 percentile of all reads; middle: NCBI reference sequence of 17q21.31 (chr17:44,191,805-44,221,804); below: sanger sequence of a break-point specific PCR on cDNA and sashimi plots depicting junction reads from RNA-Seq data of representative UBTF::ATXN7L3 patients and representative patients from other subtypes. B Basic clinical characteristics, treatment courses and outcome of UBTF::ATXN7L3 patients are shown. C Minimal residual disease (MRD) was measured by clone-specific real-time quantitative PCR of immune gene rearrangements after consolidation cycle I. Negative: MRD negative with sensitivity of at least 10−4, positive: MRD above 10−4 also including cytologic non-response, intermediate: MRD positive < 10−4 or below quantifiable range. D Overall survival analysis of UBTF::ATXN7L3 patients compared to the remaining cohort.
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