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. 2021 Aug 10;36(2):394–402. doi: 10.1038/s41375-021-01368-1

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — A Donut plot depicting the mutational status of patients at complete molecular remission (CMR). 81/150 patients (54%) had no mutation, whereas 69/150 (46%) had persistency/acquisition of single or combined mutations, for a total of 24 different groups (donut slices). B Clonal evolution analysis of NPM1^mut AML from diagnosis to CMR (n = 150 patients). Lost mutations are depicted in blue, persistent mutations in gray and acquired mutations in orange. Three main patterns emerged: mutations that were mostly or completely lost at CMR: NRAS, FLT3-TKD, STAG2, WT1, GATA2, and KRAS (all 100%), PTPN11 (95%), CEBPA (92%), IDH1 (81%), EZH2 (80%), IDH2 (71%); mutations that were mostly or exclusively acquired at CMR (TP53, CSNK1A1 and SETBP1, all 100%), and mutations with a more heterogeneous behavior: SRSF2 (mutation lost in 45% persistent in 38% and acquired in 17% of cases), TET2 (mutation lost in 52%, persistent in 31% and acquired in 17% of cases) and DNMT3A (mutation lost in 29%, persistent in 56% and acquired in 15% of cases). C Mutation frequencies of AML associated genes in relapse samples of 38/52 patients with clinical relapse. The percentage of each gene alteration among all the mutations per timepoint is depicted. *FLT3-ITD mutations were detected by gene scan. D Clonal evolution analysis of NPM1^mut AML from diagnosis to CMR and relapse (R) (n = 38 patients) allows for higher temporal resolution and identifies three main patterns: mutations which could either persist at CMR and be lost at R or completely absent at both CMR and R (BCOR, NRAS, FLT3-TKD); CHIP-like mutations present at diagnosis, CMR and R (TET2, IDH1, IDH2, DNMT3A, SRSF2); mutations with oncogenic potential: gained at CMR and persistent at R or acquired de novo at relapse (CEBPA, PTPN11, WT1, GATA2, RUNX1). E DNMT3A, TET2, IDH1, IDH2, and SRSF2 often act as foundation mutations onto which other potentially oncogenic (CHOP) hits arise as later events in AML pathogenesis. Venn diagram showing the novel proposed classification of CHIP-like mutations including: DNMT3A, TET2, IDH1, IDH2, and SRSF2, versus mutations with oncogenic potential (CHOP) in the context of NPM1^mut AML.