Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations

Abstract

Acute myeloid leukemia (AML) with t(8;21) (q22;q22) is considered to have favorable risk; however, nearly half of t(8;21) patients are not cured, and recent studies have highlighted remarkable genetic heterogeneity in this subset of AML. Here we identify somatic mutations in additional sex combs-like 2 (ASXL2) in 22.7% (25/110) of patients with t(8;21), but not in patients with inv(16)/t(16;16) (0/60) or RUNX1-mutated AML (0/26). ASXL2 mutations were similarly frequent in adults and children t(8;21) and were mutually exclusive with ASXL1 mutations. Although overall survival was similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse of 54.6% and 36.0%, respectively, compared with 25% in ASXL1/2 wild-type counterparts (P = .226). These results identify a high-frequency mutation in t(8;21) AML and identify the need for future studies to investigate the clinical and biological relevance of ASXL2 mutations in this unique subset of AML.

Figure 1

ASXL2 mutations are frequent in AML patients bearing the t(8;21) translocation and are associated with a trend for increased risk for relapse. (A) Gene diagram depicting ASXL2 mutations in adult and pediatric patients with t(8;21) AML. (B) Pattern of molecular and cytogenetic lesions in patients with t(8;21) AML. Each column represents 1 of the 110 t(8;21) AML samples sequenced here. Patient demographics (adult vs pediatric sample) are also included. Cumulative incidence of relapse according to enrollment ASXL2 and ASXL1 mutation status in (C) the entire t(8;21) AML cohort and (D) adult patients who achieved more than 3 log-fold reduction in RUNX1-RUNX1T1 transcripts before initiation of second consolidation course.