Therapy-related myeloid neoplasms (tMN) following successful treatment of acute myeloid leukemia (AML) are rare and poorly characterized. To evaluate the presence of a common ancestral clone, we performed whole-exome sequencing of 25 patients at AML diagnosis, tMN diagnosis (tMDS: 13; tAML: 12), and matched remission samples, identifying 607 mutations affecting 504 different genes (46 recurrently mutated). Number of mutations was higher in tAML vs. tMDS cases (median 19 vs 13 mutations, p = 0.05). Focusing on 24 genes commonly mutated in hematological malignancies, 19/25 (76%) patients were found to share mutations between AML and tMN, mostly affecting epigenetic modifiers (21/32; 66%), splicing factors (6/32; 19%), and chromatin modifiers (3/32; 9%). Analysis of remission samples identified 13 persisting mutations in 10/22 patients, affecting DNMT3A (n = 6), TET2 (n = 5), IDH1 and SRSF2 (n = 1, each). Comparison of cytogenetics revealed that 9/12 patients with a normal karyotype (NK) in AML harbored aberrations in tMN, four aberrant AML cases presented with NK in tMN, four other patients showed unrelated cytogenetic aberrations. Our study provides novel insights into the pathogenesis of tMN, hypothesizing the presence of a common ancestral clone in AML and tMN. Mutations mostly affected epigenetic modifiers, which have previously been linked to clonal hematopoiesis.