Frequency, Clinical Associations, and Prognostic Significance Of Spliceosome Mutations In Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia

Recurrent somatic mutation in RNA splicing machinery genes have been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). The majority of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) or with therapy-related acute myeloid leukemia (tAML) are associated with multilineage dysplasia. However, the clinical and biologic characteristics of AML-MRC and tAML with spliceosome mutations have not been elucidated. Thus, the objective of this study was to evaluate the frequency, clinical associations, and prognostic significance of spliceosome mutations in patients with AML-MRC and tAML.

A total of 224 patients were included in this study, consisting 190 cases of AML-MRC and 34 of tAML. U2AF1, SRSF2, and SF3B1 mutations are the three most frequent genes involved with spliceosome mutations in myeloid malignancies, and these mutations were detected using standard PCR techniques and direct sequencing.

Spliceosome mutations in U2AF1 (S34 and Q157), SRSF2 (P95), and SF3B1 (primarily K700E) were found in 19 (8.5%), 13 (5.8%), and 7 (3.1%) of the 224 patients, respectively. These mutations were mutually exclusive and 17.4% of the patients had one of these mutations. As shown in Table 1, patients with spliceosome mutations had a higher rate of AML-MRC, a prior history of MDS or MDS/myeloproliferative neoplasm (MPN), and intermediate cytogenetic risk compared to patients without mutations. Only one patient with tAML had a spliceosome mutation. Of the patients with AML-MRC diagnosed based solely on MDS-related cytogenetics, only one patient had the U2AF1 mutation. Within the mutation-positive patients, the U2AF1 mutation was associated with younger age (median 47 vs. 66.5 years for other types; P < 0.001), lower WBC count (median 2.4 vs. 10.75 • 10⁹/L for other types; P < 0.001), and higher rate of trisomy 8 (36.8% vs. 0.0% for other types; P = 0.003). The SRSF2 mutation was associated with normal karyotype (61.5% vs. 23.1% for other types, P = 0.03), and the SF3B1 mutation was associated with the presence of ring sideroblasts (71.4% vs. 18.8% for other types, P = 0.012) and a higher rate of complex karyotype (42.9% vs. 3.1% for other types, P = 0.01). There was a trend of male dominance (76.9%) for SRSF2 mutation and a higher frequency of adverse cytogenetic risk (57.1%) for SF3B1 mutation. At the median follow-up of 7.3 months, 122 (54.5%) deaths and 161 (71.9%) events were documented. Overall survival (P = 0.752) and event-free survival (P = 0.864) were similar among patients with or without one of the three mutations, U2AF1, SRSF2, or SF3B1 mutations.

U2AF1 was the most frequently mutated spliceosome gene among patients with AML-MRC and tAML. The association of spliceosome mutation with a preceding MDS or MDS/MPN suggests that spliceosome mutation has a unique role in the pathogenesis of progression. Although spliceosome mutations were associated with distinct clinical and biologic features in the cohort presented in this study, none of the features were prognostically relevant.

Cho:Asan Institute for Life Sciences: Research Funding. Chi:Asan Institute for Life Sciences: Research Funding. Park:Asan Institute for Life Sciences: Research Funding.