Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation

被引：97

作者：

Cocciardi, Sibylle ^{[1
]}

Dolnik, Anna ^{[1
]}

Kapp-Schwoerer, Silke ^{[1
]}

Ruecker, Frank G. ^{[1
]}

Lux, Susanne ^{[1
]}

Blaette, Tamara J. ^{[1
]}

Skambraks, Sabrina ^{[1
]}

Kroenke, Jan ^{[1
]}

Heidel, Florian H. ^{[2
,3
]}

Schnoeder, Tina M. ^{[2
,3
]}

Corbacioglu, Andrea ^{[1
]}

Gaidzik, Verena, I ^{[1
]}

Paschka, Peter ^{[1
]}

Teleanu, Veronica ^{[1
]}

Goehring, Gudrun ^{[4
]}

Thol, Felicitas ^{[5
]}

Heuser, Michael ^{[5
]}

Ganser, Arnold ^{[5
]}

Weber, Daniela ^{[1
]}

Straeng, Eric ^{[6
]}

Kestler, Hans A. ^{[6
]}

Doehner, Hartmut ^{[1
]}

Bullinger, Lars ^{[1
,7
]}

Doehner, Konstanze ^{[1
]}

机构：

[1] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany

[2] Friedrich Schiller Univ, Dept Internal Med Hematol & Oncol 2, Med Ctr, D-07743 Jena, Germany

[3] Fritz Lipmann Inst, Leibniz Inst Aging, D-07745 Jena, Germany

[4] Hannover Med Sch, Inst Cell & Mol Pathol, D-30625 Hannover, Germany

[5] Hannover Med Sch, Dept Haematol Haemostasis Oncol & Stem Cell Trans, D-30625 Hannover, Germany

[6] Ulm Univ, Inst Med Syst Biol, D-30625 Ulm, Germany

[7] Charite, Dept Hematol Oncol & Tumorimmunol, D-13353 Berlin, Germany

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

MINIMAL RESIDUAL DISEASE; YOUNGER ADULT PATIENTS; GENE-EXPRESSION; STEM-CELLS; PROGNOSTIC-SIGNIFICANCE; NORMAL CYTOGENETICS; SOMATIC MUTATIONS; AML; HEMATOPOIESIS; DNMT3A;

D O I：

10.1038/s41467-019-09745-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1(mut)) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1(mut) samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1(mut) loss (n = 11). To better understand these NPM1(mut) loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1(mut) loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1(mut) are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1(mut) loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.

引用

页数：11

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