NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia

Abstract

The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment.

Association between Immunophenotypic Parameters and Molecular Alterations in Acute Myeloid Leukemia

“…However, although many mutations in DNMT3A are cataloged, few have been thoroughly investigated, with point mutations in the catalytic domain being the major players associated with AML drivers [91]. Other studies have shown that patients with DNMT3A mutation present higher levels of HLA-DR, CLIP, PD-L1, and TIM-3 and lower levels of CD34 (Figure 2) [89,92,93]. The majority of studies in Table 1 (7/10) reported the presence of CD34+ immunophenotypic markers in most patients.…”