Correlation of Next-Generation Sequencing Based Genotypic Profiles with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia

Abstract

The purpose of this study was to analyze association between next-generation sequencing (NGS) genomic profile and conventional MICM characteristics in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1mut). We selected 238 NPM1mut patients with available NGS information on 112 genes related to blood diseases, using χ2 and Mann-Whitney U test to analyze the distribution correlation between genomic alterations and MICM parameters. Compared with NPM1mut/FLT3-ITD(−), the NPM1mut/FLT3-ITD(+) group presented a slightly common M5 [78/143 (54.5%) vs. 64/95 (67.4%); P=0.048], more higher CD34 and CD7 expression rates (CD34: 20.6% vs. 47.9%, P<0.001; CD7: 29.9% vs. 61.5%, P<0.001), and lack of favorable- and adverse-risk karyotypes (6.4% vs. 0%; P=0.031). In entire NPM1mut cohort, totaling 240 NPM1 mutation events were identified, of whom 10 (10/240, 4.2%) were missense types. When confining analysis to the 205 cases with NPM1mut insertions/deletions type and normal karyotype, multivariable logistic analysis showed that FLT3-ITD was positively correlated with CD34 and CD7 expression (HR=5.29 [95% CI 2.64-10.60], P<0.001; HR=3.47 [95% CI 1.79-6.73], P<0.001; respectively). Ras-pathway mutation was positively correlated with HLA-DR expression (HR=4.05 [95% CI 1.70-9.63], P=0.002), and KRAS mutation negatively with MPO expression (HR=0.18 [95% CI 0.05-0.62], P=0.007). DNMT3A-R882 was positively correlated with CD7 and HLA-DR expression (HR=3.59 [95% CI 1.80-7.16], P<0.001; HR=13.41 [95% CI 4.56-39.45], P<0.001; respectively). DNMT3A mutation was negatively correlated with MPO expression (HR=0.35 [95% CI 1.48-8.38], P=0.004). TET2/IDH1 mutations were negatively correlated with CD34 and CD7 expression (HR=0.26 [95% CI 0.11-0.62], P=0.002; HR=0.30 [95% CI 0.14-0.62], P=0.001; respectively), and positively with MPO expression (HR=3.52 [95% CI 1.48-8.38], P=0.004). NPM1mut co-existing mutations in signaling pathways (FLT3-ITD and Ras-pathway) and methylation modifiers (DNMT3A and TET2/IDH1) are linked with the expression of CD34, CD7, HLA-DR and MPO, thereby providing a mechanism explanation for the immunophenotypic heterogeneity of this AML entity.