[Association of Next Generation Sequencing Based Genotypic Profiling with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia].

OBJECTIVE

To explain the clinicobiological heterogeneity of NPM1 mutated (NPM1) acute myeloid leukemia (AML) by analyzing the association between next-generation sequencing (NGS) profiles and MICM characteristics in patients with this AML subtype.

METHODS

Data of 238 NPM1 patients with available NGS information on 112 genes related to blood disease was collected, and χ test and nonparametric test were used to analyze the distribution association between NGS-detecting mutations and conventional MICM parameters.

RESULTS

In entire NPM1 cohort, totaling 240 NPM1 mutation events were identified, of whom 10 (10/240, 4.2%) were missense mutations, which did not involve any W288 or W290 locus and were found exclusively in NPM1/FLT3-ITD group. All but one of these missense mutations (9/10, 90%) were accompanied by AML subtype-defining recurrent cytogenetic or molecular abnormalities, of which 7 cases were in the low risk and 2 in the high risk. NPM1 occurred solely as an insertion/deletion (indel) type in the NPM1/FLT3-ITD group. The incidence of favorable plus unfavorable karyotypes in NPM1/FLT3-ITD group was higher than in NPM1/FLT3-ITD group (6.4% vs. 0, P=0.031). The positive rates of CD34 and CD7 in NPM1/FLT3-ITD group were significantly higher than in NPM1/FLT3-ITD group (CD34: 47.9% vs. 20.6%, P<0.001; CD7: 61.5% vs. 29.9%, P<0.001). Logistic analysis showed that FLT3-ITD independently predicted for CD34 and CD7 [odds ratio (OR)=5.29, 95%CI: 2.64-10.60, P<0.001; OR=3.47, 95%CI: 1.79-6.73, P<0.001; respectively]. Ras-pathway mutations independently predicted for HLA-DR (OR=4.05, 95%CI: 1.70-9.63, P=0.002), and KRAS mutation for MPO (OR=0.18, 95%CI: 0.05-0.62, P=0.007). TET2/IDH1 mutations independently predicted for CD34 and CD7 (OR=0.26, 95%CI: 0.11-0.62, P=0.002; OR=0.30, 95%CI: 0.14-0.62, P=0.001; respectively), and MPO (OR=3.52, 95%CI: 1.48-8.38, P=0.004). DNMT3A-R882 independently predicted for CD7 and HLA-DR (OR=3.59, 95%CI: 1.80-7.16, P<0.001; OR=13.41, 95%CI: 4.56-39.45, P<0.001; respectively), and DNMT3A mutation for MPO(OR=0.35, 95%CI: 1.48-8.38, P=0.004).

CONCLUSION

Co-existing FLT3-ITD in NPM1 AML independently predicts for CD34 and CD7, co-existing Ras-pathway mutation for HLA-DR and MPO, co-existing TET2/IDH1 mutation for CD34, CD7, and MPO, and co-existing DNMT3A mutation for HLA-DR, CD7, and MPO, thereby providing a new mechanism explanation for the immunophenotypic heterogeneity of these AML patients.