Genetic Characteristics According to Subgroup of Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Abstract

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) includes heterogeneous conditions such as previous history and specific cytogenetic and morphological properties. In this study, we analyze genetic aberrations using an RNA-based next-generation sequencing (NGS) panel assay in 45 patients with AML-MRC and detect 4 gene fusions of KMT2A-SEPT9, KMT2A-ELL, NUP98-NSD1, and RUNX1-USP42 and 81 somatic mutations. Overall, all patients had genetic aberrations comprising of not only cytogenetic changes, but also gene fusions and mutations. We also demonstrated several characteristic genetic mutations according to the AML-MRC subgroup. TP53 was the most commonly mutated gene (n = 11, 24%) and all were found in the AML-MRC subgroup with myelodysplastic syndrome-defining cytogenetic abnormalities (AML-MRC-C) (p = 0.002). These patients showed extremely poor overall survival not only in AML-MRC, but also within the AML-MRC-C subgroup. The ASXL1 (n = 9, 20%) and SRSF2 (n = 7, 16%) mutations were associated with the AML-MRC subgroup with >50% dysplasia in at least two lineages (AML-MRC-M) and were frequently co-mutated (55%, 6/11, p < 0.001). Both mutations could be used as surrogate markers to diagnose AML-MRC, especially when the assessment of multilineage dysplasia was difficult. IDH1/IDH2 (n = 13, 29%) were most commonly mutated in AML-MRC, followed by CEBPA (n = 5, 11%), PTPN11 (n = 5, 11%), FLT3 (n = 4, 9%), IDH1 (n = 4, 9%), and RUNX1 (n = 4, 9%). These mutations were not limited in any AML-MRC subgroup and could have more significance as a risk factor or susceptibility marker for target therapy in not only AML-MRC, but also other AML categories.

Keywords: RNA-based next-generation sequencing; acute myeloid leukemia with myelodysplasia-related changes; morphological properties; previous history; specific cytogenetic.

Figure 1

Genetic profile of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) patients in this study. Data are shown for 45 patients. Each column represents one patient, and each row represents genetic or clinical information. Information on immunophenotypes (gray), mutations (purple), and expressions (blue) is indicated by color and color intensity. Group C: patients with myelodysplastic syndrome (MDS)-defining cytogenetic abnormalities; M: patients with >50% dysplasia in at least two lineages; H: patients with history of prior MDS or MDS/myeloproliferative neoplasm; 2017 ELN risk group was the risk category determined following the 2017 European Leukemia NET.

Figure 2

Overall survival of all patients according to AML-MRC subtype (a) in all patients, (b) among treated patients, and (c) among patients who underwent intensive chemotherapy.