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

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; Andreas E Kulozik

doi:10.3324/haematol.2015.129692

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

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 WeischenfeldtJan O Korbel, Martina U Muckenthaler, Andreas E Kulozik

51 Citations (Scopus)

Abstract

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.

Original language	English
Article number	100
Journal	Haematologica
Pages (from-to)	1442-1450
Number of pages	8
ISSN	0390-6078
DOIs	https://doi.org/10.3324/haematol.2015.129692
Publication status	Published - 31 Oct 2015
Externally published	Yes

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Kunz, J. B., Rausch, T., Bandapalli, O. R., Eilers, J., Pechanska, P., Schuessele, S., Assenov, Y., Stütz, A. M., Kirschner-Schwabe, R., Hof, J., Eckert, C., von Stackelberg, A., Schrappe, M., Stanulla, M., Koehler, R., Avigad, S., Elitzur, S., Handgretinger, R., Benes, V., ... Kulozik, A. E. (2015). Pediatric T-lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Haematologica, 1442-1450. Article 100. https://doi.org/10.3324/haematol.2015.129692

Kunz, JB, Rausch, T, Bandapalli, OR, Eilers, J, Pechanska, P, Schuessele, S, Assenov, Y, Stütz, AM, Kirschner-Schwabe, R, Hof, J, Eckert, C, von Stackelberg, A, Schrappe, M, Stanulla, M, Koehler, R, Avigad, S, Elitzur, S, Handgretinger, R, Benes, V, Weischenfeldt, J, Korbel, JO, Muckenthaler, MU & Kulozik, AE 2015, 'Pediatric T-lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation', Haematologica, pp. 1442-1450. https://doi.org/10.3324/haematol.2015.129692

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

abstract = "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, {\textquoteleft}type 1{\textquoteright} relapse derives from the primary leukemia whereas {\textquoteleft}type 2{\textquoteright} 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.",

author = "Kunz, {Joachim B} and Tobias Rausch and Bandapalli, {Obul R} and Juliane Eilers and Paulina Pechanska and Stephanie Schuessele and Yassen Assenov and St{\"u}tz, {Adrian M} and Renate Kirschner-Schwabe and Jana Hof and Cornelia Eckert and {von Stackelberg}, Arend and Martin Schrappe and Martin Stanulla and Rolf Koehler and Smadar Avigad and Sarah Elitzur and Rupert Handgretinger and Vladimir Benes and Joachim Weischenfeldt and Korbel, {Jan O} and Muckenthaler, {Martina U} and Kulozik, {Andreas E}",

note = "Copyright {\textcopyright} 2015, Ferrata Storti Foundation.",

year = "2015",

month = oct,

day = "31",

doi = "10.3324/haematol.2015.129692",

language = "English",

pages = "1442--1450",

journal = "Haematologica",

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T1 - Pediatric T-lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

AU - Kunz, Joachim B

AU - Rausch, Tobias

AU - Bandapalli, Obul R

AU - Eilers, Juliane

AU - Pechanska, Paulina

AU - Schuessele, Stephanie

AU - Assenov, Yassen

AU - Stütz, Adrian M

AU - Kirschner-Schwabe, Renate

AU - Hof, Jana

AU - Eckert, Cornelia

AU - von Stackelberg, Arend

AU - Schrappe, Martin

AU - Stanulla, Martin

AU - Koehler, Rolf

AU - Avigad, Smadar

AU - Elitzur, Sarah

AU - Handgretinger, Rupert

AU - Benes, Vladimir

AU - Weischenfeldt, Joachim

AU - Korbel, Jan O

AU - Muckenthaler, Martina U

AU - Kulozik, Andreas E

PY - 2015/10/31

Y1 - 2015/10/31

N2 - 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.

AB - 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.

U2 - 10.3324/haematol.2015.129692

DO - 10.3324/haematol.2015.129692

M3 - Journal article

C2 - 26294725

SN - 0390-6078

SP - 1442

EP - 1450

JO - Haematologica

JF - Haematologica

M1 - 100

ER -

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

Abstract

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