2p23.3

DNMT3A2,HESJAS,M.HsaIIIA,TBRS

Acute myeloid leukemia (AML)

DNMT3A mutations frequently detected in 7-29% of AML patients. This mutation was associated with normal karyotype, older age, French-American-British (FAB) M4/M5 subtypes, and poor prognosis. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for over-all survival and relapse-free survival (Hou et al., 2012; Ley et al., 2010; Thol et al., 2011a; Yan et al., 2011). This mutation was also reported in 35.1% of secondary AML and 16.4% of therapy-related AML in a study of a cohort of 98 patients and found that this mutation was associated with normal karyotype and IDH1/IDH2 mutations, but that it does not affect survival (Shih et al., 2013). Recent reports further demonstrated that the frequency of DNMT3A mutations is rare in childhood AML and MDS, suggesting that the frequency of DNMT3A gene mutation depends on age (Ho et al., 2011; Thol et al., 2011b). In addition, it was also reported that AML patients whose leukemic blasts have low DNMT3A activity, either due to loss-of-functions or low gene expression, may benefit from treatment with hypomethylating agents (Metzeler et al., 2012).

Myelodysplastic syndrome (MDS)

Mutations of the DNMT3A gene were detected in 6% of MDS patients and amino acid R882 was the most common mutation site. Patients with DNMT3A mutations had worse overall survival compared with patients without these mutations and more rapid progression to AML (Walter et al., 2011).

Myeloproliferative neoplasms (MPN)

In a study of a cohort of 155 patients with MPN, an overall frequency of 10% mutations were most frequently detected in secondary AML (sAML: 17%) and myelofibrosis (MF: 15%), followed by polycythemia vera (PV: 7%) and essential thrombocythemia (ET: 3%). These alterations occurred concurrently with JAK2, IDH1/2 and ASXL1 mutations. In addition, these mutations are associated with more advanced stages of MPNs and with an overall poor prognosis (Stegelmann et al., 2011).

T-cell lymphoma

DNMT3A mutations were reported in eleven of 98 patients with T-cell lymphoma and were associated with TET2 mutations (Couronne et al., 2012).

T-cell acute lymphoblastic leukemia (T-ALL)

DNMT3A mutations were detected in 16 of 90 patients (17.8%) with T-ALL. These alterations were associated with normal karyotype, lower hemoglobin levels and mutually exclusive in cases with CDKN2A/CDKN2B deletions. Further, these mutations had a strong association with shorter overall survival (Grossmann et al., 2013).

Lung cancer

Deletion of Dnmt3a significantly promotes tumor growth and progression in lung cancer mouse model, suggesting that this gene may act like a tumor-suppressor gene and may be a crucial factor of lung cancer malignancy (Gao et al., 2011).