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

被引:67
作者
Kunz, Joachim B. [1 ,2 ,3 ]
Rausch, Tobias [2 ,4 ,14 ]
Bandapalli, Obul R. [1 ,2 ,3 ]
Eilers, Juliane [1 ,2 ]
Pechanska, Paulina [1 ,2 ]
Schuessele, Stephanie [1 ,2 ]
Assenov, Yassen [5 ]
Stuetz, Adrian M. [2 ,4 ]
Kirschner-Schwabe, Renate [6 ]
Hof, Jana [3 ,6 ,7 ]
Eckert, Cornelia [6 ]
von Stackelberg, Arend [6 ]
Schrappe, Martin [8 ]
Stanulla, Martin [9 ]
Koehler, Rolf [10 ]
Avigad, Smadar [11 ,12 ]
Elitzur, Sarah [11 ,12 ]
Handgretinger, Rupert [13 ]
Benes, Vladimir [14 ]
Weischenfeldt, Joachim [4 ]
Korbel, Jan O. [4 ]
Muckenthaler, Martina U. [1 ,2 ]
Kulozik, Andreas E. [1 ,2 ,3 ]
机构
[1] Heidelberg Univ, Childrens Hosp, Dept Pediat Oncol Hematol & Immunol, D-69115 Heidelberg, Germany
[2] Heidelberg Univ, EMBL, Mol Med Partnership Unit, D-69115 Heidelberg, Germany
[3] German Canc Consortium DKTK, Heidelberg, Germany
[4] European Mol Biol Lab, Genome Biol Unit, D-69012 Heidelberg, Germany
[5] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany
[6] Charite Univ Med Berlin, Dept Pediat Oncol Hematol, Berlin, Germany
[7] German Canc Res Ctr, Heidelberg, Germany
[8] Univ Hosp Schleswig Holstein, Pediat, Kiel, Germany
[9] Hannover Med Sch, Dept Pediat Hematol Oncol, Hannover, Germany
[10] Heidelberg Univ, Dept Human Genet, D-69115 Heidelberg, Germany
[11] Schneider Childrens Med Ctr Israel, Felsenstein Med Res Ctr, Mol Oncol, Petah Tiqwa, Israel
[12] Schneider Childrens Med Ctr Israel, Pediat Hematol Oncol, Petah Tiqwa, Israel
[13] Univ Tubingen Hosp, Childrens Hosp, Tubingen, Germany
[14] European Mol Biol Lab, Genom Core Facil, D-69012 Heidelberg, Germany
基金
欧洲研究理事会;
关键词
ACUTE MYELOID-LEUKEMIA; DNA METHYLATION DATA; ACTIVATING MUTATIONS; SOMATIC MUTATIONS; GENOMIC ANALYSIS; CHILDHOOD; RISK; RESISTANCE; LANDSCAPE; CHILDREN;
D O I
10.3324/haematol.2015.129692
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1442 / 1450
页数:9
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