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

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: GIGYF2, DHX15, and G2E3. 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/RTKmutated 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 RUNX1-RUNX1T1 in quantitative polymerase chain reaction analysis. KIThigh 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; P = .005). Together with age and white blood cell counts, JAK2, FLT3-internal tandem duplicationhigh, and KIThigh 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.

The clinical mutatome of core binding factor leukemia

“…S7). In contrast to recent reports [8,20,21], the mutational burden of KIT D816 mutations was not relevant when assessing the prognostic impact of this mutation in our cohort ( Supplementary Fig. S8).…”

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

“…On average, the number of mutations was similar at diagnosis and relapse in all cohorts, although in FLT3-ITD positive AML, a lower mutational load at relapse was reported, 37 while in the CN-AML cohort, the mutation load increased. 41 The frequency of transversions (C > A and C > G changes) was commonly higher among relapse-specific mutations, 37,41,42,44 which is in line with previous reports and may be due to the mutagenic effect of cytarabine treatment. 36,46 Of note, this was not observed in APL, however, APL treatment does not include cytarabine.…”

Dynamic Clonal Hematopoiesis and Functional T-cell Immunity in a Super-centenarian

“…This aggressive expansion parallels patterns of clonal evolution otherwise observed in overt myeloid disease, i.e. myelodysplastic syndromes [ Silvas-Coelho 2017 , Makishima 2017], myeloproliferative neoplasms [Lundberg 2014] or relapsed acute myeloid leukemia [Ding 2012, Christen 2019], in which subclonal lineages may completely replaced. Whether these complete wipeouts occur within the healthy aged hematopoietic stem cell compartment remains to be determined.…”