Abstract
Mutations in DNA methyltransferase 3A (DNMT3A) gene were recently demonstrated in acute myeloid leukemia(AML). Approximately 20% patients with AML carry DNMT3A gene mutations and was associated with a poor clinical outcome. but its clinical implications in Chinese AML patients are largely unknown. We analyzed 101 adult AML patients in china and found 14 patients (13.9%) harboring this mutation. 9 patient with M5, 2 patients with M1, 2patient with M2 and 1 patient with M3. We identified 11 missense mutation,2 nonsense and 30 bp deletion encompassing DNMT3A. The most common of them was predicted to affect 882Arg(in 4 patients). Double mutations were detected in two cases.10 of 33(43.5%). DNMT3A mutations occurred more frequently in older (age > 50y,p < 0.05) and the outcome is too badly for these patients. We concluded that DNMT3A mutations are highly recurrent in AML and is associated with distinct clinical and biologic characteristics and seems to be a useful as a prognostic marker.
Highlights
Acute Myeloid Leukemia (AML) is a heterogeneous malignancy that can be classified by morphological, cytogenetic and molecular genetic criteria, Currently, cytogenetic analysis at diagnosis allows for risk-stratification of AML into a useful prognostic marker and intermediate risk [1], To some extent, Treatment protocols are adapted in an attempt to improve survival and decrease treatment-related toxicity
Gene mutation in DNA methyltransferase which alter enzyme function have been described in acute leukemia, Yamashita et al reported [5] 4.1% somatic mutation of DNA methyltransferase (DNMT3A) at amino-acid Arg882 in leukemia, Later Ley [6] et al found 22.1% DNA methyltransferase 3A (DNMT3A) mutations in adult normal karyotype AML genome and Chen SJ discovered gene mutations in DNMT3A in patients with M5 (20.5%) and with 13.6% of M4 subtype [7]. those results above indicated that DNMT3A mutations were independently and significantly associated with decreased survival in adult AML. in order to analyze the influence of DNMT3A mutation on the prognosis and survival of AML
DNMT3A mutations In my study, 101 samples from new diagnostic AML were detected by PCR amplification of entire coding region of DNMT3A, the detection rate of DNMT3A mutations in AML patients was 13.9%(14/101), including 2 patients of M1, 2 patients of M2,1 patient of M3 and 9 patients of M5(42.9%). (Table1) .the type of mutations was 11 missense, 2 nonsense and 1 deletion mutations.respectively. single nucleotide variations included 2645 G > A(Arg882His), 914 G > A, 2096 G > A(Gly699Asp), 2501C > T(Thr834IIe), 55C > T(Arg19Trp), 2202C > A(Phe734Leu) and 2644 C > T(Arg882Cys).(,Fig-1) The most common mutations are predicted to affect amino- acid Arg882 and Thr834(in 2 patients).We detected a 30 bp deletion according to sequencing (Figure 1, patient 40)
Summary
Acute Myeloid Leukemia (AML) is a heterogeneous malignancy that can be classified by morphological, cytogenetic and molecular genetic criteria, Currently, cytogenetic analysis at diagnosis allows for risk-stratification of AML into a useful prognostic marker and intermediate risk [1], To some extent, Treatment protocols are adapted in an attempt to improve survival and decrease treatment-related toxicity. Gene mutation in DNA methyltransferase which alter enzyme function have been described in acute leukemia, Yamashita et al reported [5] 4.1% somatic mutation of DNA methyltransferase (DNMT3A) at amino-acid Arg882 in leukemia, Later Ley [6] et al found 22.1% DNMT3A mutations in adult normal karyotype AML genome and Chen SJ discovered gene mutations in DNMT3A in patients with M5 (20.5%) and with 13.6% of M4 subtype [7]. Those results above indicated that DNMT3A mutations were independently and significantly associated with decreased survival in adult AML. In order to analyze the influence of DNMT3A mutation on the prognosis and survival of AML. RNA from bone marrow cells of untreated AML patients from the Chinese patients were examined by using PCR and sequence analysis, simultaneously chromosome examination and immunophenotype were performed
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