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Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission an...

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Main Authors: Kunz, Joachim (Author) , Rausch, Tobias (Author) , Bandapalli, Obul Reddy (Author) , Eilers, Juliane (Author) , Richter-Pechańska, Paulina (Author) , Schüssele, Stephanie (Author) , Assenov, Yassen (Author) , Stütz, Adrian M. (Author) , Kirschner-Schwabe, Renate (Author) , Hof, Jana (Author) , Eckert, Cornelia (Author) , Stackelberg, Arend von (Author) , Schrappe, Martin (Author) , Stanulla, Martin (Author) , Köhler, Rolf (Author) , Avigad, Smadar (Author) , Elitzur, Sarah (Author) , Handgretinger, Rupert (Author) , Benes, Vladimir (Author) , Weischenfeldt, Joachim (Author) , Korbel, Jan Oliver (Author) , Muckenthaler, Martina (Author) , Kulozik, Andreas (Author)
Format: Article (Journal)
Language:English
Published: October 31, 2015
In: Haematologica
Year: 2015, Volume: 100, Issue: 11, Pages: 1442-1450
ISSN:1592-8721
DOI:10.3324/haematol.2015.129692
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.3324/haematol.2015.129692
Verlag, lizenzpflichtig, Volltext: http://www.haematologica.org/content/100/11/1442
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Author Notes:Joachim B. Kunz, Tobias Rausch, Obul R. Bandapalli, Juliane Eilers, Paulina Pechanska, Stephanie Schuessele, Yassen Assenov, Adrian M. Stütz, Renate Kirschner-Schwabe, Jana Hof, Cornelia Eckert, Arend von Stackelberg, Martin Schrappe, Martin Stanulla, Rolf Koehler, Smadar Avigad, Sarah Elitzur, Rupert Handgretinger, Vladimir Benes, Joachim Weischenfeldt, Jan O. Korbel, Martina U. Muckenthaler, and Andreas E. Kulozik
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Summary:Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, ‘type 1’ relapse derives from the primary leukemia whereas ‘type 2’ relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition.
Item Description:Gesehen am 03.06.2020
Physical Description:Online Resource
ISSN:1592-8721
DOI:10.3324/haematol.2015.129692

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