Journal Article

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

Takeuchi, M, Chiba, K, Yoshida, K, Imai, K, Oshima, M, Hirase, C, Okumura, H, Yokote, K, Ogawa, S, Togasaki, E, Morishita, Y, Usui, N, Ohnishi, K, Miyazaki, Y, Matsumura, I, Nakaseko, C, Ohtake, S, Sakaida, E, Naoe, T, Asou, N, Iwama, A, Saraya, A, Fujisawa, S, Kobayashi, Y, Miyano, S, Takahashi, N, Kiyoi, H, Tanaka, H, Shiraishi, Y, Takeda, J, Takeshita, A, Shiozawa, Y

2017

Overview

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1–17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 ( P =0.0381). Mutations in epigenetic regulator, ASXL1 , TET2 , TET3 , KDM1A and MSH6 were found in 25% of patients. TET2 or TET3 , AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1 .

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 631/67/1990 / 692/699/1541 / Age Factors / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell division / Dioxygenases - genetics / DNA Copy Number Variations - genetics / DNA-Binding Proteins - genetics / Drug Resistance, Neoplasm - genetics / Epigenesis, Genetic - genetics / Epigenetics / Female / Fusion Proteins, bcr-abl - genetics / Hematology / Histone Demethylases - genetics / Humans / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology / Leukocyte Count / Male / Mutation / Oncology / Original / original-article / Protein Kinase Inhibitors - administration & dosage / Proto-Oncogene Proteins - genetics / Repressor Proteins - genetics / Signal Transduction / Whole Exome Sequencing