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

Biao Wang; Yun Ling; Li Dai; Wei-ying GU; Xiu-wen Zhang; Shan-shan Xing; Hai-qian LI

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

Author: Biao WANG ¹ ; Yun LING ¹ ; Li DAI ¹ ; Wei-Ying GU ¹ ; Xiu-Wen ZHANG ² ; Shan-Shan XING ³ ; Hai-Qian LI ⁴
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1. Department of Hematology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), Changzhou 213003, Jiangsu Province, China.
2. Department of Hematology, Nanjing Medical University Affiliated Changzhou Second Hospital, Changzhou 213164, Jiangsu Province, China.
3. Department of Hematology, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China.
4. Department of Hematology, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), Changzhou 213003, Jiangsu Province, China,E-mail: lhz0125@163.com.
Publication Type:Journal Article
Keywords: FLT3-ITD; NPM1; acute myeloid leukemia; immunophenotype; next generation sequencing
MeSH: High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute/genetics*; Mutation; Nuclear Proteins/genetics*; Nucleophosmin; Prognosis; fms-Like Tyrosine Kinase 3/genetics*
From: Journal of Experimental Hematology 2022;30(1):56-60
CountryChina
Language:Chinese
Abstract: OBJECTIVE:To explain the clinicobiological heterogeneity of NPM1 mutated (NPM1^mut) 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^mut patients with available NGS information on 112 genes related to blood disease was collected, and χ² test and nonparametric test were used to analyze the distribution association between NGS-detecting mutations and conventional MICM parameters.
RESULTS:In entire NPM1^mut 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^mut/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^mut occurred solely as an insertion/deletion (indel) type in the NPM1^mut/FLT3-ITD⁺ group. The incidence of favorable plus unfavorable karyotypes in NPM1^mut/FLT3-ITD^- group was higher than in NPM1^mut/FLT3-ITD⁺ group (6.4% vs. 0, P=0.031). The positive rates of CD34 and CD7 in NPM1^mut/FLT3-ITD⁺ group were significantly higher than in NPM1^mut/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^mut 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.