TET2, ANPM1 and FLT3-ITD Gene Mutations in Normal Karyotype Acute Myeloid Leukemia

Analyze the molecular genetics characteristics of acute myeloid leukemia with normal karyotype and explore the relationship between different genetic mutation patterns and prognosis.

A total of 373 acute myeloid leukemia (AML) with normal karyotype diagnosed and treated in the First Affiliated Hospital of Soochow University from 2005 to 2010 were recruited in this research to assess the genetic mutation patterns. The target genes which was extracted from bone marrow cell were amplified by PCR and analyzed by massively DNA sequencing. All of the TET2, DNMT3A, IDH1, IDH2, EZH2, CBL, ASXL1, MLL-PTD, NPM1, WT1, RUNX1, c-KIT, FLT3-ITD, FLT3-TKD, N-RAS and JAK2V617F gene mutations were detected in our study.

(1). A total of 16.1% of patients had TET2 mutations, 31.6% had FLT3 internal tandem duplications (ITDs), 6.2% had FLT3 tyrosine kinase domain mutations, 2.4% had c-KIT mutations, 37.8% had NPM1 mutations, 11.3% had WT1 mutations, 5.9% had RUNX1 mutations, 11.5% had ASXL1 mutations, 3.8% had MLL partial tandem duplications (PTDs), 7.8% had IDH1 mutations, 7.8% had NRAS mutations, 12.3% had IDH2 mutations, 1.6% had EZH2 mutations, 14.7% had DNMT3A mutations and no mutations were found of CBL and JAK2V617F. In conclusion, there are 77% (287/373) gene mutations hide in normal karyotype AML patients.(2). We found that the TET2 gene mutations were associated with DNMT3A (P = 0.041) and RUNX1 (P <0.001) mutations, but mutually exclusive with IDH2 (P = 0.021), or IDH1/2 (P = 0.006) gene mutations. NPM1 gene mutations were highly correlated with DNMT3A mutations (P <0.0001), IDH1 mutations (P <0.0001) and IDH2 mutations (P = 0.001), but mutually exclusive with RUNX1 mutations (P=0.003). IDH2 mutations and WT1 mutations were mutually exclusive (P = 0.01); DNMT3A mutations were associated with NRAS mutations (P = 0.01). In addition, study have shown that the number of gene mutations was closely associated with older age, high white blood cell and high bone marrow blast cell percentage, but wasn't correlated with gender, hemoglobin and platelet levels.(3). In the NPM1m+ patients, TET2 mutations were associated with shorter median OS in contrast to TET2 wild type (9.9 vs. 27.0 months, P= 0.023). Surprisingly, in NPM1m+/FLT3-ITDm- group, TET2 mutations was also an unfavorable prognostic factor, which was closely associated with shorter median OS compared to TET2 wild type (9.5 vs. 32.2 months, P=0.013).

Gene mutations incidence was high in normal karyotype AML patients. TET2 mutations was an unfavorable prognostic factor which was closely associated with shorter median OS in contrast to TET2 wild type in NPM1m+/FLT3-ITDm-group. In addition, The number of gene mutation was closely associated with older age, high white blood cell levels and high bone marrow blast cell percentage.

No relevant conflicts of interest to declare.