Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients

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Item Type:	Article
Title:	Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients
Creators Name:	Christen, F., Hoyer, K., Yoshida, K., Hou, H.A., Waldhueter, N., Heuser, M., Hills, R.K., Chan, W., Hablesreiter, R., Blau, O., Ochi, Y., Klement, P., Chou, W.C., Blau, I.W., Tang, J.L., Zemojtel, T., Shiraishi, Y., Shiozawa, Y., Thol, F., Ganser, A., Löwenberg, B., Linch, D.C., Bullinger, L., Valk, P.J.M., Tien, H.F., Gale, R.E., Ogawa, S. and Damm, F.
Abstract:	Acute myeloid leukemia with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40% of patients. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least 1 mutation, in addition to t(8;21), was identified in 95%, with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10.3%), and the spliceosome (7.9%). Our study identified mutations in previously unappreciated genes: , , and Based on high mutant levels, pairwise precedence, and stability at relapse, epigenetic regulator mutations were likely to occur before signaling mutations. In 34% of RAS/RTK patients, we identified multiple mutations in the same pathway. Deep sequencing (∼42 000×) of 126 mutations in 62 complete remission samples from 56 patients identified 16 persisting mutations in 12 patients, of whom 5 lacked in quantitative polymerase chain reaction analysis. mutations defined by a mutant level ≥25% were associated with inferior relapse-free survival (hazard ratio, 1.96; 95% confidence interval, 1.22-3.15; = .005). Together with age and white blood cell counts, , -internal tandem duplication, and mutations were identified as significant prognostic factors for overall survival in multivariate analysis. Whole-exome sequencing was performed on 19 paired diagnosis, remission, and relapse trios. Exome-wide analysis showed an average of 16 mutations with signs of substantial clonal evolution. Based on the resemblance of diagnosis and relapse pairs, genetically stable (n = 13) and unstable (n = 6) subgroups could be identified.
Keywords:	flt3 Gene, Genes, Genome, Acute Myeloid Leukemia, Ms-Like Tyrosine Kinase 3, Mutation, runx1 Translocation Partner 1 Protein, Whole Exome Sequencing, Heterogeneity, Disease Remission
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	133
Number:	10
Page Range:	1140-1151
Date:	7 March 2019
Official Publication:	https://doi.org/10.1182/blood-2018-05-852822
PubMed:	View item in PubMed

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