Clinical Characteristics and Outcomes of Acute Myeloid Leukemia Patients Harboring NPM1/FLT3-ITD/DNMT3A Triple Mutations and the Potential Prognostic Value of GNG4.

Abstract

IntroductionNucleophosmin 1 (NPM1), FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), and de novo methyl transferase 3 A (DNMT3A) triple-mutated acute myeloid leukemia (AML) represents a distinct entity with poor outcomes.MethodsWe explored the gene mutation spectrum and clinical characteristics of 165 AML patients retrospectively, particularly comparing patients with NPM1/FLT3-ITD/DNMT3A triple-mutations and those without.ResultsOur results demonstrated significantly elevated white blood cell counts (P < 0.001), bone marrow blast percentages (P = 0.037), and platelet counts (P = 0.007) in the triple-mutated cohort (6.7%) compared to the non-triple-mutated patients. Furthermore, all triple-mutated cases were classified as the M4/M5 subtype of the French-American-British classification (P = 0.017). Although no significant difference in complete remission rates was observed between the groups after initial treatment, the median overall survival for triple-mutated AML patients was only 4 months. Using the Gene Expression Omnibus (GEO) database and bioinformatics, we compared AML^{NPM1mutFLT3-ITDmutDNMT3Amut} and AML^{NPM1mutFLT3-ITDmutDNMT3Awt}. A total of 246 AML patients from the GEO dataset were included to evaluate the expression profiles of differentially expressed genes. The guanine nucleotide-binding protein subunit γ 4 (GNG4) was differentially expressed between AML^{NPM1mutFLT3-ITDmutDNMT3Amut} and AML^{NPM1mutFLT3-ITDmutDNMT3Awt}, which had the most adjacent nodes among hub genes. The prognostic value of GNG4 was further validated in AML patient samples through qRT-PCR.ConclusionClinical validation indicated a substantial downregulation of GNG4 in AML^{NPM1mutFLT3-ITDmutDNMT3Amut} compared to AML^{NPM1mutFLT3-ITDmutDNMT3Awt} patients. Thus, GNG4 may play a role in the low survival rate of AML^{NPM1mutFLT3-ITDmutDNMT3Amut} patients, offering novel insights into the prognosis, therapeutic targets, and prognostic evaluation of AML.