Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Acute myeloid leukaemia: recent data on prognostic gene mutations, in relation to stratified therapies for elderly patients.

TET2 protein is encoded by the gene TET2 which specifically catalyses the demethylation of 5-methylcytosine to cytosine. Mutations in TET2 have been identified in a number of haematological malignancies, including leukaemias and lymphomas. In acute myeloid leukaemia (AML), loss of TET2 function drives DNA methylation and gene silencing, contributing to disease pathogenesis and progression, making it an interesting target. Although such mutations are considered rare, there is an increasing body in the literature identifying them as unfavourable prognostic markers in AML. The hypomethylating agent nucleoside analogue 5-azacytidine is used in the treatment of AML and other haematological malignancies i.e. myelodysplastic syndrome (MDS). It functions by re-activating silenced genes is responsible for cytosine methylation, thereby driving differentiation and also promoting apoptosis of dysfunctional haematological cells. The present review article deals with the consequences of DNA methylation in relation to TET2 in AML, focusing on the potential prognostic effect of TET2 gene mutations, along with demethylating epigenetic strategies towards prediction of therapeutic response. The necessity for personalized therapeutic regimes, especially for older patients suffering from AML with mutated TET2 and/or other genetic alterations, along with its prognostication are also underlined.