Abstract
ObjectiveThis study aimed to evaluate DNMT3A exon 23 mutations and their prognostic impacts in the presence of NPM1 and FLT3 mutations in acute myeloid leukemia (AML) patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).Materials and MethodsThis study comprised 128 adult AML patients referred to the Hematology-Oncology and Stem Cell Research Center of Shariati Hospital. NPM1 and FLT3-ITD mutations were detected by fragment analysis. For DNMT3A exon 23 mutation analysis, we used Sanger sequencing. Overall survival (OS) and relapse-free survival (RFS) curves were estimated by the Kaplan-Meier method and the log-rank test was used to calculate differences between groups.ResultsThe prevalence of DNMT3A exon 23 mutations was 15.6% and hotspot region R882 mutations were prominent. RFS and OS were compared in patients with and without DNMT3A exon 23 mutations using univariate analysis and there was no significant difference between these groups of patients. On the contrary, the FLT3-ITD mutation significantly reduced the OS (p=0.009) and RFS (p=0.006) in AML patients after allogeneic HSCT. In the next step, patients with AML were divided into four groups regarding FLT3-ITD and DNMT3A mutations. Patients with DNMT3A R882mut/FLT3-ITDpos had the worst OS and RFS. These results indicate that DNMT3A mutations alone do not affect the clinical outcomes of AML patients undergoing allogeneic HSCT, but when accompanied by FLT3-ITD mutations, the OS was significantly reduced (5-year OS 0% for DNMT3A R882mut/FLT3-ITDpos patients vs. 62% DNMT3A R882wt/FLT3-ITDneg, p=0.025) and the relapse rate increased.ConclusionIt can be deduced that DNMT3A R882mut/FLT3-ITDpos is an unfavorable prognostic factor in AML patients even after allogeneic HSCT.
Highlights
Acute myeloid leukemia (AML) is considered a clonal disorder of the hematopoietic stem cells marked by proliferation of immature myeloid cells in the bone marrow (BM) or peripheral blood
Patients with DNMT3A R882mut/FLT3-ITDpos had the worst Overall survival (OS) and relapse-free survival (RFS). These results indicate that DNMT3A mutations alone do not affect the clinical outcomes of AML patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), but when accompanied by FLT3-ITD mutations, the OS was significantly reduced
It can be deduced that DNMT3A R882mut/FLT3-ITDpos is an unfavorable prognostic factor in AML patients even after allogeneic HSCT
Summary
Acute myeloid leukemia (AML) is considered a clonal disorder of the hematopoietic stem cells marked by proliferation of immature myeloid cells in the bone marrow (BM) or peripheral blood. Cell signaling abnormalities, and epigenetic modification affect the destination of hematopoietic stem cells and could lead to leukemogenesis [1,2]. Standard induction chemotherapy, which is a combination of cytarabine and anthracyclines, induces a high rate of complete remission (CR) in patients with AML; the rate of relapse is high. This is more pronounced in elderly patients. Risk stratification is one of the most important applications of molecular abnormalities, in determining risk stratification after CR is achieved by induction therapy, and it is important because it prevents the referral of patients to hematopoietic stem cell transplantation (HSCT) centers [4]. Epigenetic regulation refers to the modification of gene transcription and expression in such a way that the genetic code does not change [5]
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